South Africa has one of the highest burdens of tuberculosis and drug-resistant tuberculosis in the world. In the past decade, the number of cases of XDR tuberculosis has increased by a factor of 10, to more than 1500 cases in 2012. Compounding the tuberculosis epidemic is the concurrent epidemic of HIV infection; rates of coinfection exceed 70%, and rates of long-term survival among patients with XDR tuberculosis and HIV infection are less than 20%. In this study, we sought to quantify the role of transmission and to elucidate how and where transmission is occurring. We combined traditional epidemiologic tools with social-network, geospatial, and genotyping methods to describe population-level transmission of XDR tuberculosis.