As English colonists expanded westward in the late 17th and 18th centuries, the Indian trail gradually became a more clearly defined roadway.

First on horseback, and then in stage coaches and wagons, in colonial times, travelers from the ports of Alexandria and Georgetown (then in Maryland) followed it to Winchester at the lower end of the Shenandoah Valley for trade.

Along the way, small settlements sprang up which provided lodging and provisions for travelers and trade centers for local farmers.

During the American Civil War, the roads which became US 50 were an important travelway for troops, and were the site of significant battles and skirmishes.

During the 19th century, the Virginia Board of Public Works encouraged and helped finance internal transportation improvements such as canals, turnpikes, and some of the earlier railroads.

It is on a winding, two lane road until it passes the former lumbering town of Gore, at which point it widens to a four-lane highway.

During the American Civil War, Colonel John Singleton Mosby was a Confederate partisan who operated with great success in this region, gaining status as a local folk-hero.

The highway passes across the southeastern portion through the Town of Middleburg, and the communities of Aldie (birthplace of Stonewall Jackson's mother, Julia Beckwith Neale), Gilberts Corner, Arcola, and South Riding.

Continuing east from the border with Loudoun County, US 50, Lee-Jackson Memorial Highway, travels along the historic Little River Turnpike route.

It passes by the southern edge of Washington Dulles International Airport and the Steven F. Udvar-Hazy Center and through the communities of Chantilly and Fair Oaks.

Shortly after entering the independent city of Fairfax, US 50 leaves Little River Turnpike (its original route until 1935, which continues as Virginia State Route 236) and joins a concurrency with US 29 as Fairfax Boulevard (a new designation, concurrent with the old names Main Street, Lee Highway, and Arlington Boulevard).