The CR&E Division is a vital link between the midwest and southeast. The route's western end is in the Kanawha Valley at Charleston, WV. The railroad's business in this area is based heavily on coal and chemicals. Interchanges with CSX's C&O Business Unit and Conrail's West Virginia Secondary are important for traffic into and out of the area. The Conrail route is very important because it links the CR&E at Charleston with the rest of the Norfolk Southern system at Columbus, OH. Several trains use the trackage rights agreement with Conrail between Columbus and Charleston.

At Fayetteville, WV, the CR&E maintains a yard and servicing facility to keep equipment available for the many mines runs that haul coal out of the New River field. Further east, at Springdale, WV, is an important connection with CSX's former Nicholas, Fayette & Greenbrier route. The NF&G was at one time jointly owned by the Chesapeake & Ohio and New York Central (later CSX and Conrail). CSX coal shifters now converge on Rainelle, WV, a yard north of Springdale on the NF&G, to assemble trains that will travel CR&E Division rails toward the Shenandoah Valley.

Lewisburg, WV, is the site of a moderate-sized classification yard and servicing facility. At approximately the midway point between Charleston and Danville, the town of Lewisburg became an important division point for the Charleston, Roanoke & Eastern. The railroad had a backshop and carshop here for major repairs. Today these shops are owned by an equipment leasing and rebuilding company which has maintained the railroad's namesake, CR&E Leasing (CREX). A significant amount of local traffic is worked out of Lewisburg. Several mine runs are based here as well, serving a mainline loadout at Caldwell, WV, as well as branchline flood-loaders on the Laurel Creek and Potts Creek branches east of here.

Shenandoah Junction, VA, is an important connection point with CSX's Shenandoah Division. Here, CSX's coal for southern destinations leaves the CR&E mainline and heads south toward Salem, VA, and Hamlet, NC.

Roanoke, VA, is the site of a huge Norfolk Southern hump classification yard. It is also the site of a smaller CR&E yard where some trains set off and pick up to avoid the congestion of the main yard.  The mainline heads southeast from here toward Danville, VA, where it connects with the former Southern Railway mainline. Several CR&E Division trains head south of here to Linwood, NC, where NS maintains a large hump yard.