U.S. Route 15 (US 15) is a part of the United States Numbered Highway System that runs from Walterboro, South Carolina, north to Painted Post, New York. In Maryland, the highway runs 37.85 miles (60.91 km) from the Virginia state line at the Potomac River in Point of Rocks north to the Pennsylvania state line near Emmitsburg. Known for most of its length as Catoctin Mountain Highway, US 15 is the primary north–south highway of Frederick County. The highway connects the county seat of Frederick with Point of Rocks, Leesburg, Virginia, and Charles Town, West Virginia, to the south and with Thurmont, Emmitsburg, and Gettysburg, Pennsylvania, to the north. US 15 is an expressway throughout the state except for the portion south of MD 28. The highway is a freeway along its concurrency with US 340 and through Frederick, where the highway meets US 40 and Interstate 70 (I-70). US 15 has a business route through Emmitsburg.

U.S. Route 340 is a spur route of US 40, and runs from Greenville, Virginia, to Frederick, Maryland. In Virginia, it runs north–south, parallel and east of US 11, from US 11 north of Greenville via Waynesboro, Grottoes, Elkton, Luray, Front Royal, and Berryville to the West Virginia state line. A short separate piece crosses northern Loudoun County on its way from West Virginia to Maryland.