On July 26, 1856, the Pittsburgh, Fort Wayne and Chicago Rail Road was formed as a consolidation of the Fort Wayne and Chicago, Ohio and Indiana, and Ohio and Pennsylvania Railroads. Extensions opened west to Warsaw September 28, Plymouth November 10, Englewood, Illinois (south of Chicago) on November 29, 1858, and Van Buren Street in Chicago on December 25, 1858. On January 1, 1859, trains started running to Chicago, with a terminal at the future location of Union Station. The part west of Plymouth was built with rails removed from the New Portage Railroad.
From the early days, the Pennsylvania Railroad (PRR) had been involved with the project, supplying funds. Once the Fort Wayne Railroad Bridge at Pittsburgh was finished in 1857, trains began to run through from Philadelphia. In 1858 the PFW&C began using the first Union Station in Pittsburgh, shared with the PRR.
On July 1, 1859, the PFW&C defaulted on its debts, and was sold at foreclosure on October 24, 1861. It was reorganized as the Pittsburgh, Fort Wayne and Chicago Railway February 26, 1862.
On July 1, 1869, the PRR leased the PFW&C and began operating it directly, but on April 1, 1871, the PFW&C was transferred to the newly formed Pennsylvania Company. On December 1, 1871, the Pennsylvania Company leased the Cleveland and Pittsburgh Railroad. Since January 25, 1860, the C&P had been operated jointly by itself and by the PFW&C, providing a branch of the PFW&C from Rochester, Pennsylvania, west and north, crossing the PFW&C at Alliance, Ohio, and continuing to Cleveland.
Operation was transferred back to the Pennsylvania Railroad from the Pennsylvania Company on January 1, 1918.