The city is located at an important crossroads at the intersection of a major north–south Native American trail and east–west routes to the Chesapeake Bay, both at Baltimore and what became Washington, D.C., and across the Appalachian Mountains to the Ohio River watershed.

to the western Piedmont in North Carolina, or traveling down other watersheds in Virginia toward the Chesapeake Bay, such as those of the Rappahannock, James, and York Rivers.

The current town's first house was built by a young German Reformed schoolmaster from the Rhineland Palatinate named Johann Thomas Schley (died 1790), who led a party of immigrants (including his wife, Maria Von Winz) to the Maryland colony.

The Palatinate settlers bought land from Dulany on the banks of Carroll Creek, and Schley's house stood at the northwest corner of Middle Alley and East Patrick Street into the 20th century.

Schley's group was among the many Pennsylvania Dutch (ethnic Germans) (as well as Scots-Irish and French and later Irish) who migrated south and westward in the late-18th century.

Other westward migrants continued south from Frederick to Roanoke along the Great Wagon Road, crossing the Appalachians into Kentucky and Tennessee at the Cumberland Gap near the Virginia/North Carolina border.

In 1793, All Saints Church hosted the first confirmation of an American citizen, by the newly consecrated Episcopal Bishop Thomas Claggett.

Frederick also hosted several hospitals to nurse the wounded from those battles, as is related in the National Museum of Civil War Medicine on East Patrick Street.

A legend related by John Greenleaf Whittier claimed that Frederick's Pennsylvania Dutch women (including Barbara Fritchie who reportedly waved a flag) booed the Confederates in September 1862, as General Stonewall Jackson led his light infantry division through Frederick on his way to the battles of Crampton's, Fox's and Turner's Gaps on South Mountain and Antietam near Sharpsburg.

Confederate troops under Jackson and Walker unsuccessfully attempted to halt the Federal army's westward advance into the Cumberland Valley and towards Sharpsburg.

At the Prospect Hall mansion off Jefferson Street to Buckeystown Pike near what is now Butterfly Lane, in the early morning hours of June 28, 1863, a messenger arrived from President Abraham Lincoln and General-in-Chief Henry Halleck, informing General George Meade that he would be replacing General Joseph Hooker after the latter's disastrous performance at Chancellorsville in May.

A large granite rectangular monument made from one of the boulders at the "Devil's Den" in Gettysburg to the east along the driveway commemorates the midnight change-of-command.

In July 1864, in the third Southern invasion, Confederate troops led by Lieutenant General Jubal Early occupied Frederick and extorted $200,000 ($3.9 million in 2023 dollars[31]) from citizens in exchange for not razing the city on their way to Washington, D.C.[32] Union troops under Major General Lew Wallace fought a successful delaying action, in what became the last significant Confederate advance at the Battle of Monocacy, also known as the "Battle that Saved Washington."

The reconstructed home of Barbara Fritchie stands on West Patrick Street, just past Carroll Creek linear park.

British Prime Minister Winston Churchill quoted Whittier's poem to President Franklin D. Roosevelt when they stopped here in 1941 on a car trip to the presidential retreat, then called "Shangra-La" (now "Camp David") within the Catoctin Mountains near Thurmont.

After the Civil War, the Maryland legislature established racially segregated public facilities by the end of the 19th century, re-imposing white supremacy.

[47] Frederick's relative proximity to Washington, D.C., has always been an important factor in the development of its local economy, along with the presence of Fort Detrick, its largest employer.

The Frederick Historic District in the city's downtown houses more than 200 retailers, restaurants and antique shops along Market, Patrick and East Streets.

[49] Restaurants feature a diverse array of cuisines, including Italian American, Thai, Vietnamese, and Cuban, as well as a number of regionally recognized dining establishments.

A growing technology sector can be found in downtown's historic renovated spaces, as well as in new office buildings located along Carroll Creek Park.

[49] It was an effort to reduce the risk to downtown Frederick from the 100-year floodplain and restore economic vitality to the historic commercial district.

Today, more than $150 million in private investing is underway or planned in new construction, infill development or historic renovation in the park area.

The scale of the older part of the city is dense, with streets and sidewalks suitable for pedestrians, and a variety of shops and restaurants, comprising what Forbes magazine in 2010 called one of the United States' "Greatest Neighborhoods".

Frederick is the home of The Delaplaine Visual Arts Education Center, a leading non-profit in the region,[55] as well as the Maryland Shakespeare Festival.

[56] The Maryland Ensemble Theatre (MET), a professional theater company, is housed on the lower level of the Francis Scott Key Hotel.

The MET first produced mainstage theater in 1997, but the group began performing together with its creation of The Comedy Pigs sketch comedy/improv troupe in April 1993.

The carillon can be heard from anywhere in Baker Park, and the city carillonneur can be seen playing in the tower once a year as part of the Candlelight tour of Historic Houses of Worship, on the first weekday after Christmas.

Frederick also has a large amphitheater in Baker Park, which features regular music performances of local and national acts, particularly in the summer months.

[64] Other denominations represented in Frederick City and in the surrounding county include large numbers of Brethren, as well as some Pentecostal churches.

Frederick's location as a crossroads has been a factor in its development as a minor distribution center both for the movement of people in Western Maryland, as well as goods.