Interstate 20 (I‑20) is a major east–west Interstate Highway in the Southern United States. I‑20 runs 1,539 miles (2,476 km) through 6 states beginning near Kent, Texas, at I-10 to Florence, South Carolina, at I-95. Between Texas and South Carolina, I‑20 runs through northern Louisiana, central Mississippi, northern Alabama, and northern Georgia.

The major cities that I-20 connects to includes (from west to east) Fort Worth, Texas; Dallas, Texas, Shreveport, Louisiana, Jackson, Mississippi, Birmingham, Alabama, Atlanta, Georgia, Augusta, Georgia, Columbia, South Carolina and Florence, South Carolina.

From its eastern terminus at I‑95, the highway continues about 2 miles (3.2 km) eastward into the city of Florence South Carolina.

I-20 enters Georgia near Tallapoosa and after passing through western Georgia, it enters the Atlanta metropolitan area before meeting I-285 (the "Atlanta Bypass"). On clear days, eastbound motorists get their first view of downtown Atlanta as they come over the top of the Six Flags Hill. The Six Flags Over Georgia amusement park is easily visible off exit 46 eastbound. The highway then passes through the center of Atlanta, meeting with I-75 and I-85, which share a common expressway (the "Downtown Connector"). It continues through Metropolitan Atlanta eastward and through the eastern half of Georgia until it exits the state, crossing the Savannah River at Augusta after meeting its spur route I-520.

Interstate 25 is a major Interstate Highway in the western United States. It is primarily a north–south highway, serving as the main route through New Mexico, Colorado, and Wyoming. I-25 stretches from Interstate 10 at Las Cruces, New Mexico, to Interstate 90 in Buffalo, Wyoming.

Interstate 35 serves the heartland of America, connecting South Texas with the Arrowhead of Minnesota. Starting in Laredo, IH 35 ventures north through an arid region to San Antonio, where it briefly overlaps with Interstate 10 by Downtown. The freeway angles northeast from there along a busy corridor to the capital city of Austin, Waco and Hillsboro where it partitions into east and west branches. Interstate 35W serves Fort Worth while Interstate 35E retains the exit numbering scheme of IH 35 through Dallas. The two reconvene at Denton, where IH 35 resumes a northward heading to Gainesville and a crossing of the Red River into Oklahoma.

Leaving the Lone Star State behind, Interstate 35 travels north to Ardmore and the scenic Arbuckle Mountains ahead of Pauls Valley. The freeway continues to Norman, home of the University of Oklahoma, and Moore, a south suburb of Oklahoma City. Once in OKC, I-35 overlaps with I-40 to the southeast of Downtown and with I-44 from Lake Aluma to Lake Arcadia.

Spanning eight states Interstate 40 is a major cross-country freeway connecting the Desert Southwest with the Southeastern United States. Starting in Barstow, California, the freeway generally follows the alignment of Historic U.S. 66 across the Mojave Desert into the high desert. Spanning the Colorado River west of Kingman, I-40 gains elevation on a course south of the Grand Canyon to the city of Flagstaff. Advancing east across New Mexico, the freeway spans the width of the state, converging with Interstate 25 in Albuquerque.

Continuing to Amarillo, Interstate 40 transitions into the Great Plains in eastern New Mexico, leading into the Texas Panhandle. The freeway splits from Historic U.S. 66 at Oklahoma City, remaining generally eastward while U.S. 66 diverges northeast toward Tulsa, St. Louis and Chicago. Entering Arkansas, Interstate 40 trends southeast from Fort Smith along the Oklahoma state line to Little Rock. The freeway follows U.S. 70 east from the capital city to West Memphis. A short concurrency with I-55 precedes the Hernando DeSoto Bridge taking I-40 across the Mississippi River.

Through Memphis, I-40 follows the northern arc of the inner beltway; the southern half is I-240. The original planned alignment took I-40 across the city, using Sam Cooper Boulevard, a partially completed freeway/boulevard spur from the east toward Overton Park. Leaving Memphis, I-40 heads to Jackson and then Nashville, where it briefly overlaps with both I-65 and I-24. I-40 joins Nashville with Knoxville, merging with I-75 along an eight to ten lane freeway leading into the metropolitan area from Farragut.

Turning along a southeasterly course, Interstate 40 traverses the Great Smoky Mountains into North Carolina. Spanning nearly the width of the Tar Heel State, I-40 connects regional cities in western parts of the state including Asheville, Hickory and Statesville with the Triad area (WinstonSalem and Greensboro). Combining with I-85, I-40 proceeds east to Durham, where it turns southward for the remainder of its 420 mile route in North Carolina to Raleigh and Wilmington.

Interstate 55 parallels the Mississippi River for much of its length. The route originates at Interstate 10 outside the city of La Place, located west of New Orleans in the Delta region. The freeway runs northward along an isthmus between Lakes Maurepas and Pontchartrain between LaPlace and Ponchatola. This section of Interstate 55 is elevated. Meeting I-12 at Hammond, I-55 transitions into a forested freeway to McComb and Brookhaven in southern Mississippi.

Interstate 74 combines with I-55 to the west of Bloomington while I-39 ends from the north at Normal. Interstate 55 continues northeast from there to Joliet (I-80) and the Stephenson Expressway leading into Chicago. The northern terminus of I-55 is in Downtown Chicago at Lake Shore Drive (U.S. 41) near the sprawling McCormick Place, the city’s convention center.

Interstate 65 (I-65) is a major north–south Interstate Highway in the central United States. It also serves as one of the main north/south routes through Nashville, Tennessee; Louisville, Kentucky and Indianapolis, Indiana; each a major metropolitan area in its respective state.

Interstate 70 traverses nearly the width of the U.S., passing through 10 states and serving major metropolitan areas such as Denver, Kansas City, St. Louis, Indianapolis, Columbus and Baltimore. The west end of the freeway connects with Interstate 15 at Cove Fort, Utah.

Leaving the Denver metropolitan area, Interstate 70 traverses the Great Plains from Eastern Colorado into Kansas. The route through the Midwest crosses the width of Missouri, Illinois and Indiana.

Through Ohio, Interstate 70 crosses Dayton and Columbus, then briefly enters West Virginia at Wheeling. Entering Pennsylvania, Interstate 70 merges with the Pennsylvania Turnpike (I-76) and separates at Breezewood. I-70 traffic must follow U.S. 30 through the business district in Breezewood to connect with the freeway leading south to Maryland from the PA Turnpike. There are no plans to create a direct connection between Interstates 70 and 76.

Within the St. Louis metropolitan area, Interstate 70 was realigned to cross the Mississippi River via the four lane Stan Musial Veterans Memorial Bridge. Located north of both the existing Martin Luther King Bridge and the Poplar Street Bridge (which is now designated as just I- 55/64 and U.S. 40), the new cable-stayed bridge stems east from an extended Interstate 44 at a new interchange with Tucker Boulevard to arc southward to East St. Louis, Illinois at the tri-level interchange where I-55 and I-64 part ways.

The freeway for Interstate 70 ends at a Park and Ride in Baltimore.

Interstate 75 is a major transportation corridor, linking the Southeastern U.S. and the Great Lakes. The highway runs the length of the Florida peninsula from the Miami area and up the Gulf Coast through Naples, Fort Myers, Sarasota, Tampa, and Gainesville. Farther north, in Georgia, I-75 continues on through Macon and Atlanta before running through Chattanooga and Knoxville and the Cumberland Mountains in Tennessee. Interstate 75 runs from Cincinnati to Toledo by way of Dayton in the U.S. state of Ohio. The highway enters the state running concurrently with I-71 from Kentucky on the Brent Spence Bridge over the Ohio River and into the Bluegrass region.

Interstate 80 is a major transcontinental corridor connecting California and New York City and passes through 11 states. From the city of San Francisco to a few miles west of the Hudson River in northern New Jersey, I-80 traverses various terrain and generally very high traffic. Its highest point is located at Sherman Hill Summit in Wyoming between Laramie and Cheyenne at an elevation of 8640 feet. The highest point of Interstate 80 east of the Mississippi is near Milepost 111 in Pennsylvania.

Although Interstate 80 begins at U.S. 101 in San Francisco, original plans called for the route to continue west through Golden Gate Park to the Pacific Ocean near the famous Ocean Beach area. This plan was halted due to community opposition.

In the east, I-80 ends at Interstate 95 along the Teaneck Township and Ridgefield Park line in New Jersey.

Interstate 85 (I-85) is a major Interstate Highway in the Southeastern United States. Its current southern terminus is at an interchange with I-65 in Montgomery, Alabama; its northern terminus interchanges with I-95 in Petersburg, Virginia, near Richmond. Interstate 85 traverses a good portion of the Appalachian piedmont, as it provides a major travel corridor between the Deep South and Mid Atlantic Regions. The increasingly busy trucking corridor connects the major metropolitan areas of Atlanta and Charlotte. In addition, Interstate 85 links several smaller growing metropolitan areas including Greenville-Spartanburg, the Triad (Greensboro), and the Triangle (Durham).

The longest route within the Interstate Highway System, I-90 serves major northern cities such as Seattle, Chicago, Cleveland, Buffalo and Boston, regional cities and travels through 13 states along its transcontinental route from the Pacific Northwest to the Rocky Mountains and Great Plains including Spokane, Billings, Sheridan, Rapid City and Sioux Falls. The freeway traverses several mountain passes along the northern tier.

Interstate 95 (I-95) is the main Interstate Highway on the East Coast of the United States, running from U.S. Route 1 (US 1) in Miami, Florida to the Houlton–Woodstock Border Crossing with New Brunswick, Canada. The highway runs largely parallel to the Atlantic Ocean coast and US 1, serving areas from Florida to Maine. The East Coast’s Main Street, Interstate 95 serves the entire Northeast Megalopolis, while also serving southeastern cities of Jacksonville and Miami along Florida’s east coast. The highway is an important factor in commerce and tourism, linking scenic New England with the subtropical environs of southern Florida. It passes through more states than any other Interstate highway.