In 1849, Lieutenant Simpson made his first journey into the American west, during an expedition commanded by Colonel John James Abert.
Simpson then assumed responsibility as the Chief Topographical Engineer for the Ninth Military Department, based in Santa Fe.
Once completed, Simpson was order to make a preliminary reconnaissance into the Great Salt Lake Desert, which he commenced on 19 October.
Simpson's Central Route played a vital role in the transportation of mail, freight, and passengers between the established eastern states and California, especially when hostilities of the Civil War closed the Butterfield Overland Mail stagecoach route that ran along the southern border states.
George Chorpenning immediately switched to Simpson's route to run his existing mail and stage line, and the Pony Express used it as well.
Afterwards, Wells Fargo & Co. hauled mail, freight, and passengers along Simpson's route until 1869, when transportation and telegraphy were switched to the newly completed Transcontinental Railroad.
During the American Civil War, Simpson served as colonel of the 4th New Jersey Volunteer Infantry and was captured at the Battle of Gaines's Mill.