Evidence-based research now allows clear separation of syphilis from other diseases in its class of treponematoses. Examination of skeletons from populations with clinically diagnosed bejel and yaws revealed bone alterations distinctive to those diseases, clearly separating them from alterations due to syphilis, transcending the limitations of current DNA and immunologic technologies. These insights allowed confident identification of the New World origin of syphilis. Absence of skeletal evidence of any treponemal disease in continental Europe before the time of Columbus excludes it as site of origin of syphilis. Treponemal disease appears to have originated in East Africa with late transmission to England, perhaps as a complication of the slave trade. The original treponemal disease apparently spread from Africa through Asia, entering North America. Approximately 8 millennia later, it mutated to syphilis. Presence of skeletal evidence of syphilis at the site in the Dominican Republic where Columbus landed suggests the route by which it was transmitted to the Old World.