Mycobacterium tuberculosis (MTB), an acid-fast bacterium, is a leading cause of respiratory illness and death worldwide. Individuals can be latently infected and can harbor the organism without clinical evidence of disease for years. Screening and treatment of numerous populations, including health care workers, recent contacts of actively infected individuals, immunocompromised individuals, children, and immigrants from countries where MTB is endemic, is essential to eradicate the infection by 2050, as the World Health Organization envisions. Detection of active and latent infection historically has utilized tuberculin skin tests and other clinical findings. Interferon gamma release assays can test whether a patient has had MTB exposure with improved sensitivity and specificity over tuberculin skin testing. This article reviews the history of MTB testing, compares available interferon gamma release assays, and discusses the new developments related to latent-MTB infection testing.