Its common 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.

Further extensions west from Cadiz Junction opened June 22 to Masterville, July 12 to Bowerston, and April 11, 1855, the rest of the way to Newark.

On December 25, 1854, the S&I came to an agreement with the Central Ohio Railroad to use its tracks from Newark west to Columbus.

The full P&S opened October 9, 1865, from Smithfield Street in Pittsburgh west to Wheeling Junction at the east end of the Steubenville Railroad Bridge.

From then until 1868, the line was operated as the Pittsburgh, Columbus and Cincinnati Railroad by the Western Transportation Company.

On April 30, 1868, the PHRy, S&I and HCRR merged to form the Pittsburgh, Cincinnati and St. Louis Railway, and the Western Transportation Company was dissolved soon after.

On January 20, 1851, that section, from Indianapolis east to the Ohio state line, was renamed the Indiana Central Railway.

On January 31, an Ohio law authorized the Dayton and Western Railroad to unite with the Indiana Central and operate jointly.

The CP&I was sold at foreclosure on August 6, 1863, and reorganized October 30 as the Columbus and Indianapolis Railroad.

The R&C opened in early 1863, and the Indiana Central's joint operating contract with the Dayton and Western Railroad was dissolved on March 9.

On February 26, 1853, it was renamed the Cincinnati, Logansport and Chicago Railway to better reflect its expanded role.

The unfinished line between Richmond and Logansport was leased to John W. Wright and Company on October 16, 1856.

That line was sold at foreclosure on April 28, 1860, and reorganized July 10 as the Cincinnati and Chicago Air-Line Railroad.

On September 25, 1857, the Chicago and Cincinnati Railroad was chartered in Indiana to build a line from Logansport northwest to Valparaiso.

After several reorganizations, the Toledo, Logansport and Burlington Railroad opened to the Illinois state line near Effner in 1859.

On December 1, 1869 (retroactive from February 23, 1870) the Pittsburgh, Cincinnati and St. Louis Railway leased the Little Miami Railroad.

The Columbus, Chicago and Indiana Central Railway went bankrupt and was sold at foreclosure on January 10, 1883.

From there to the Sheraden neighborhood of Pittsburgh, the railway forms part of Norfolk Southern's Mon Line.

The portion from Sheraden to Carnegie, Pennsylvania, has been converted into the West Busway, a bus-only roadway.

The section from Carnegie to Walkers Mill, Pennsylvania, retains its rails and is owned by the Pittsburgh and Ohio Central Railroad, however, it has not seen a train since mid 2015, and it will likely be removed to become part of the Panhandle Trail.