Colonial medical reports claimed that tuberculosis (TB) was largely unknown in Africa prior to European contact, providing a “virgin soil” for spread of TB in highly susceptible populations previously unexposed to the disease [1 and 2]. This is in direct contrast to recent phylogenetic models which support an African origin for TB [3, 4, 5 and 6]. To address this apparent contradiction, we performed a broad genomic sampling of Mycobacterium tuberculosis in Ethiopia. All members of the M. tuberculosis complex (MTBC) arose from clonal expansion of a single common ancestor [ 7] with a proposed origin in East Africa [ 3, 4 and 8]. Consistent with this proposal, MTBC lineage 7 is almost exclusively found in that region [ 9, 10 and 11]. Although a detailed medical history of Ethiopia supports the view that TB was rare until the 20th century [12], over the last century Ethiopia has become a high-burden TB country [13]. Our results provide further support for an African origin for TB, with some genotypes already present on the continent well before European contact. Phylogenetic analyses reveal a pattern of serial introductions of multiple genotypes into Ethiopia in association with human migration and trade. In place of a “virgin soil” fostering the spread of TB in a previously naive population, we propose that increased TB mortality in Africa was driven by the introduction of European strains of M. tuberculosis alongside expansion of selected indigenous strains having biological characteristics that carry a fitness benefit in the urbanized settings of post-colonial Africa.