In 1837, the Michigan Southern was chartered to build a line across the Southern Tier of Michigan to the shore of Lake Michigan at New Buffalo. Construction got as far as Hillsdale, Michigan before the road was sold to private interests. The MS was combined with the Erie & Kalamazoo, and was extended west to meet the Northern Indiana Railroad. The line was opened from Monroe to South Bend in 1851, and reached Chicago by 1852. A joint Chicago terminal was opened with the Chicago, Rock Island & Pacific at LaSalle Street Station. In 1855, the MS, the E&K, and the NIR were combined as the Michigan Southern & Northern Indiana. At the same time, a route from Elkhart to Toledo was completed.
East of Toledo, the issue of uncomon railroad gauges made expansion difficult. By 1853, the NYC controlled the Buffalo & State Line and the Erie & Northeast railroads. They were combined as the Buffalo & Erie in 1867. The Cleveland, Painesville & Ashtabula, also known as the "Lake Shore," opened between Erie and Cleveland in 1852. In 1869, the Lake Shore acquired the Cleveland & Toledo, and merged with the MS&NI to become the Lake Shore & Michigan Southern. Cornelius Vanderbilt acquired the line shortly after.
In 1914, the New York Central & Hudson River Railroad and the Lake Shore & Michigan Southern, along with several smaller roads, were combined to form the New York Central Railroad.