Tuberculosis (TB) has afflicted humankind throughout history. Approximately one third of the world's population is currently infected with Mycobacterium tuberculosis and nearly two million people die of TB annually. Although much has been learned about the structure of the tubercle bacillus, the epidemiology of TB, the physiological and immunological responses of the host to infection, and the physiology of M. tuberculosis in laboratory broth cultures, much of the basic biology of M. tuberculosis in its natural setting (the infected human) remains to be elucidated. Within the past decade, there have been remarkable advances in the development of genetic and molecular biological tools with which to study M. tuberculosis. This review discusses the approaches that have been employed and the progress that has been made in discovering how M. tuberculosis has achieved its prowess as a successful pathogen.