The relative contribution of reactivated and recently acquired tuberculosis to the disease burden in developing countries is unknown, as are the settings within which most transmission occurs. In an attempt to answer these questions, we combined molecular techniques (restriction fragment length polymorphism analysis) and conventional epidemiology (risk factor analysis and contact tracing) to study 246 consecutive cases of smear-positive tuberculosis in rural South Africa. We estimate that 29-43% of the cases were recently acquired, as they were clustered. We were unable to identify firm transmission links between 73% of clustered cases. Our findings suggest that most smear-positive tuberculosis in rural Africa is both recently acquired and casually transmitted. Tuberculosis control may depend more on promoting early presentation, rapid diagnosis and vaccine development than on chemotherapy.