Interstate 64 in the context of Louisville metropolitan area

Interstate 95 (I-95) is the main north–south Interstate Highway on the East Coast of the United States, running from U.S. Route 1 (US 1) in Miami, Florida, north to the Houlton–Woodstock Border Crossing between Maine and the Canadian province of New Brunswick. The highway largely parallels the Atlantic coast and US 1, except for the portion between Savannah, Georgia, and Washington, D.C., and the portion between Portland and Houlton in Maine, both of which follow a more direct inland route.

I-95 serves as the principal road link between the major cities of the Eastern Seaboard. Major metropolitan areas along its route include Miami, Jacksonville, and Savannah in the Southeast; Richmond, Washington, Baltimore, Wilmington–Philadelphia, Newark, and New York City in the Mid-Atlantic; and New Haven, Providence, Boston, and Portland in New England. The Charleston, Wilmington, and Norfolk–Virginia Beach metropolitan areas, the three major coastal metros bypassed by the highway's inland portion, are connected to I-95 by I-26, I-40, and I-64, respectively.

U.S. Route 50 or U.S. Highway 50 (US 50) is a major east–west route of the U.S. Highway system, stretching 3,019 miles (4,859 km) from Interstate 80 (I-80) in West Sacramento, California, to Maryland Route 528 (MD 528) in Ocean City, Maryland, on the Atlantic Ocean. Until 1972, when it was replaced by Interstate Highways west of the Sacramento area, it extended (by way of Stockton, the Altamont Pass, and the Bay Bridge) to San Francisco, near the Pacific Ocean. The Interstates were constructed later and are mostly separate from this route. It generally serves a corridor south of I-70 and I-80 and north of I-64 and I-40.

The route runs through mostly rural desert and mountains in the western United States, with the section through Nevada known as "The Loneliest Road in America". In the Midwest, US 50 heads through mostly rural areas of farms as well as a few large cities including Kansas City, Missouri; St. Louis, Missouri; and Cincinnati, Ohio.