The Kansas City, Fort Scott and Memphis Railroad was the result of twenty years of railroad construction in southern Missouri and Arkansas, beginning with the organization of the Kansas and Neosho Railroad by local investors in 1865. This road was reorganized in 1868 as the Missouri River, Fort Scott and Gulf Railroad Company and was again reorganized in 1879. The resulting corporate combination included several branch lines and was styled the Kansas City, Fort Scott and Gulf Railroad Company. The line reached Springfield, Missouri, from Fort Scott, Kansas, via leased lines. The Kansas City, Springfield and Memphis Railroad built the line from Springfield to Memphis, completed in 1883. The entire system, known as the "Memphis Route," was consolidated by agreement in 1888 as the Kansas City, Fort Scott and Memphis Railroad Company.

The Memphis Route competed with the St. Louis and San Francisco Railway Company ("Frisco") for control of some of the same territory and branch lines. The Frisco expanded rapidly during the 1890s, and in 1901 gained control of the Fort Scott system. Formal ownership was assumed in 1928.

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