Latent tuberculosis infection (LTBI) is a clinical condition characterized by a positive tuberculin skin test in the absence of clinical or radiological signs of active tuberculosis disease. It has been estimated that one third of the world's population is latently infected with Mycobacterium tuberculosis and serves as an enormous reservoir for future cases of active tuberculosis. The detection and treatment of individuals with LTBI and a high risk of progression to active tuberculosis are effective means to control the spread of tuberculosis. Furthermore, a better understanding of the host-pathogen interactions that result in latent infection could provide important insights for future drug or vaccine development. This chapter reviews recent developments in the molecular genetics, natural history, diagnosis, and treatment of LTBI within its historical context, including the impact of human immunodeficiency virus infection. Current treatment recommendations are also summarized.