A profusion of articles have been published on the accuracy and uses of interferon-gamma releasing assays. Here we review the clinical applications, advantages, and limitations of the tuberculin skin test and interferon-gamma release assays and provide an overview of the most recent systematic reviews conducted for different indications for the use of these tests. We conclude that both tests are accurate to detect latent tuberculosis, although interferon-gamma release assays have higher specificity than tuberculin skin testing in BCG-vaccinated populations, particularly if BCG is received after infancy. However, both tests perform poorly to predict risk for progression to active tuberculosis. Interferon-gamma release assays have significant limitations in serial testing because of spontaneous variability and lack of a validated definition of conversion and reversion, making it difficult for clinicians to interpret changes in category (conversions and reversions). So far, the most important clinical evidence, that is, that isoniazid preventive therapy reduces the risk for progression to disease, has been produced only in tuberculin skin test-positive individuals.