Extensively drug-resistant tuberculosis (XDR-TB) is defined as Mycobacterium tuberculosis infection that is resistant to isoniazid, rifampin, any fluoroquinolone, and any injectable drug (amynoglicosides or polypetides). Although initially described in South Africa, it has emerged as a global threat, and cases have been reported from several countries, including the United States. XDR-TB has emerged mainly as a consequence of previous inadequate or poorly administered treatment, from failure of the public health infrastructure. As the diagnosis of this condition requires antibiotic susceptibility confirmation, a broad network of reference laboratories and the development of faster and more accurate tests for the identification of active cases of tuberculosis are urgently required. The treatment of XDR-TB is challenging and requires the use of multiple second-line drugs and, potentially, surgery. Infection control measures do not differ from those used for susceptible cases but may require more stringent application.