Treatment of latent tuberculosis infection (LTBI) is considered an essential component of TB control programs in several industrialized countries and is being used in selected situations in developing countries. In 2000, the American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC) published new recommendations on the diagnosis and treatment of LTBI. These guidelines emphasized targeted tuberculin testing as a means of diagnosis in populations at risk, and expanded the choice of drug regimens to be used for treatment. After the implementation of the recommendations, unexpected and serious hepatic injury with the use of rifampin and pyrazinamide occurred, resulting in a modification of the recommendations. This article reviews the populations who should be considered for targeted tuberculin testing, scientific rationale for the selected treatment regimens, recently completed studies related to rifampin and pyrazinamide, and the prior and updated recommendations for treatment of LTBI.