PA 100 intersects several important highways, including US 30 in Exton, the Pennsylvania Turnpike (I-76) near Lionville, US 422 near Pottstown, US 222 in Trexlertown, and I-78/US 22 in Fogelsville.

Several sections of PA 100 are multi-lane divided highway with some interchanges, including between US 202 and the Pennsylvania Turnpike in Chester County between south of Pottstown and New Berlinville, and between Trexlertown and Fogelsville.

The southern terminus of PA 100 was moved from Delaware Route 100 (DE 100) at the state line, and placed at the south end of the freeway connector to US 202, in 2003 in order to reduce through traffic in West Chester.

The route curves to the northwest and continues near suburban residential and commercial development, turning to the west and intersecting PA 113 in Lionville.

The road passes near business parks and enters Upper Uwchlan Township as it crosses under the Pennsylvania Turnpike and reaches Eagle.

The route becomes a three-lane road with a center left-turn lane as it passes commercial development and comes to an intersection with PA 401 in the village of Ludwigs Corner.

Following this, PA 100 becomes a two-lane road and runs through a mix of farmland and woodland, crossing into East Nantmeal Township.

The route continues through rural areas with some development, crossing French Creek and passing through Pughtown before it comes to the PA 23 junction in Bucktown.

[2][3] After this intersection, PA 100 heads north through wooded areas with some farm fields and residences as a three-lane road with a center turn lane.

The road crosses Pigeon Creek into North Coventry Township and passes farm fields before entering commercial areas.

At this point, the road becomes a partially controlled access highway with at-grade intersections, some grade separations, and no private driveways.

The route comes to an interchange with PA 724 to the west of South Pottstown and to the east of the Coventry Mall.

[2][4] Upon crossing County Line Road, PA 100 enters Colebrookdale Township in Berks County and heads north through rural areas with some development as an unnamed road, curving northwest to an interchange with Montgomery Avenue near New Berlinville that provides access to Boyertown and PA 562.

Following this interchange, the partially controlled access highway section ends as the route narrows to a two-lane undivided road and passes by businesses.

PA 100 turns to the northeast and passes through a mix of woods and fields with some residential and commercial development, heading to the west of Grandview Speedway.

The route begins a winding path to the northwest as it descends a hill through a mix of farms and trees.

The route crosses Norfolk Southern's Reading Line at-grade and Swabia Creek, passing more commercial establishments as it enters Lower Macungie Township and becomes an unnamed road.

The road heads west through a mix of farmland and residential and commercial development, curving to the northwest and losing the center turn lane.

The route continues northwest near farmland and residential subdivisions into Upper Macungie Township and intersects Weilers Road, which heads north to Hamilton Boulevard.

[2][6] US 222 and PA 100 continue north concurrent as a four-lane divided expressway called the Frederick J. Jaindl Jr. Memorial Highway, passing near homes and intersecting Grim Road/Cetronia Road at-grade.

The route runs north-northwest through a mix of farm fields and an industrial/warehouse area as an unnamed four-lane divided highway.

The road enters Lowhill Township and runs through a mix of farmland and woodland with some development, passing through Claussville.

The route followed the Brandywine Creek through Chadds Ford to Lenape, where it ran concurrent with PA 52 to West Chester.

[31][32] In 1988, plans were made to bypass the section of PA 100 through Eagle which was narrow and suffered from traffic congestion.

A bypass to the east of Trexlertown was proposed as opposed to adding turn lanes along the existing route as the latter would have required the demolition of several buildings.

In 2003, the southern terminus of PA 100 was moved from the Delaware border to its current location at US 202, being rerouted to follow the freeway connecting US 202 to Exton.

PA 100 was truncated in order to reduce truck traffic along rural roads and on the streets through West Chester.

[36] The former route of PA 100 between the Delaware border and Exton was designated SR 3100 in Chester County and SR 3101 in Delaware County, which follows Chadds Ford Road, Creek Road, PA 52, US 322 Bus., North High Street, and Pottstown Pike.