In December 1873, at age 30, Simpson left Canada and assumed the pulpit of the largest Presbyterian church in Louisville, Kentucky, the Chestnut Street Presbyterian Church. It was in Louisville that he first conceived of preaching the gospel to the common man by building a simple tabernacle structure for that purpose. Despite his success at the Chestnut Street Church, Simpson was frustrated by their reluctance to embrace this burden for wider evangelistic endeavor.
Simpson's heart for evangelism was to become the driving force behind the creation of the C&MA. Initially, the Christian and Missionary Alliance was not founded as a denomination, but as an organized movement of world evangelism. Today, the C&MA denomination plays a leadership role in global evangelism.