The emergence of multidrug resistant (MDR) strains of Mycobacterium tuberculosis (MDR-TB) represents a serious worldwide threat to the health of mankind. Approximately 2 billion persons are infected with Mycobacterium tuberculosis, and 8.8 million new cases of tuberculosis occur annually, with over 50,000 attributable deaths each week! Drug resistance is either acquired with the initial infection (from a host harboring resistant tubercle bacilli) or develops during treatment with antituberculous chemotherapeutic agents because of poor patient compliance or inadequate/inappropriate treatment regimens. The epidemiology of tuberculosis and drug resistance is reviewed; the likelihood of the development of resistance and the molecular mechanisms of resistance to each drug are also discussed. Principles of prevention of nosocomial transmission, use of involuntary detention, and drug treatment approaches for MDR-TB are discussed, and the potential roles of surgery and novel therapies (phenothiazines, suicide genes) are presented.