Mycobacterium tuberculosis (MTB) remains a worldwide health care challenge despite the relatively recent evolution of effective antituberculous medications and combination drug therapy. In many parts of the world, the continued high prevalence of MTB disease is caused in part by the lack of availability of medications and the growing problem of multidrug-resistant TB (MDR-TB). In the United States, however, errors in treatment constitute a significant portion of treatment failures and relapses. The eradication of MTB in the United States is an achievable goal through the strict adherence to several treatment principles that have been developed over the latter half of the 20th century. These include (1) the use of multiple drugs to which the organism is sensitive; (2) using these drugs in appropriate combinations for a sufficient period of time; (3) using directly observed therapy whenever possible; (4) using in vitro drug susceptibility and local resistance patterns to guide initial drug choices; and (5) never adding a single drug to a failing regimen. Strict adherence to these principles along with an emphasis on completing the total number of doses for a particular regimen will help to ensure fewer relapses/failures, achieve higher cure rates, and help eradicate MTB disease in this country.