Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis have emerged as important infections in South Africa among patients infected with human immunodeficiency virus (HIV). In the face of this new epidemic, South Africa must rededicate itself to the task of tuberculosis control and treatment with a rapid, multifaceted approach. Priorities include expansion of second-line treatment capacity, investment in clinical laboratories, a system to ensure supervised treatment for all patients, and enhancement of infection control procedures. In New York City, where drug-resistant tuberculosis emerged 2 decades ago—also in the context of a large HIV-infected population and an underfunded public health infrastructure—similar steps were successful in leading to the rapid decrease in rates of drug resistance among tuberculosis isolates. With refinements based on local resource constraints, urgent measures could potentially arrest the alarming increase in multidrug-resistant and extensively drug-resistant tuberculosis cases in South Africa. Unlike many countries in sub-Saharan Africa, South Africa has the capacity to mount a rapid and large-scale response before drug-resistant tuberculosis envelops a much larger and far poorer region.