Although 13 cases of cross-species transmission of a simian immunodeficiency virus (SIV) into humans have been reported, only HIV-1 group M has led to a pandemic. Oliver Pybus, Philippe Lemey and colleagues now report a phylogenomic analysis of HIV-1 sequences isolated from central Africa, providing insights into what distinguished the origins and spread of HIV-1 group M (Science 346, 56–61, 2014). They examined the sequences of 348 HIV-1 group M viruses from the Democratic Republic of Congo (DRC) as well as 466 viruses from neighboring countries, obtained from the Los Alamos HIV Sequence Database. Their phylogenetic analysis estimates the time of the most recent common ancestor of HIV-1 group M sequences to be approximately 1920, confirming previous studies. They further localized the spatial origin of group M to Kinshasa in the DRC, from which virus spread to the southern DRC locations of Lubumbashi and Mbuji-Mayi, both mining towns that are connected by rail routes that likely facilitated dissemination. HIV-1 group O, which has remained non-pandemic and localized to west-central Africa, emerged at a similar time and showed similar growth rates until 1960, when the growth rate of group M viruses nearly tripled. The authors suggest that changes in health care practices might have influenced the increased spread of group M, but further studies are needed to characterize what distinguished the epidemiological courses of these HIV-1 lineages.