On September 30, 1890, the Chicago, St. Louis and Pittsburgh Railroad; the Pittsburgh, Cincinnati & St. Louis Railroad; the Cincinnati and Richmond Railroad and the Jeffersonville, Madison and Indianapolis Railroad were merged to form the Pittsburgh, Cincinnati, Chicago and St. Louis Railway (PCC&StL).

In 1891, the PCC&StL acquired stock ownership of the Little Miami Railroad. On December 21, 1916 (taking effect January 1, 1917), the Pittsburgh, Cincinnati, Chicago and St. Louis Railway merged with the Vandalia Railroad, Pittsburgh, Wheeling and Kentucky Railroad, Anderson Belt Railway and Chicago, Indiana and Eastern Railway, forming the Pittsburgh, Cincinnati, Chicago and St. Louis Railroad.

The PCC&StL was leased by the Pennsylvania Railroad on January 1, 1921, and finally was merged into the PRR's Philadelphia, Baltimore and Washington Railroad on April 2, 1956.

The line was commonly called the Pan Handle Route.

The name came from its main line, which began at Pittsburgh, Pennsylvania, crossed the Northern Panhandle of West Virginia, and continued west to Bradford, Ohio, where it split into a northern line to Chicago and a southern one through Indianapolis, Indiana, to East St. Louis, Illinois.