Mycobacterium tuberculosis, the causative agent of tuberculosis, has infected billions of people worldwide. A key to the success of M. tuberculosis and related pathogenic mycobacteria lies in their ability to persist within the hostile environment of the host macrophage. After internalization by macrophages, most microbes are rapidly transported to lysosomes in which they are destroyed. By contrast, pathogenic mycobacteria prevent fusion of phagosomes with lysosomes, thereby surviving intracellularly. Recent progress in understanding the molecular biology of host-mycobacteria interactions is providing insights into these survival tactics.