Tuberculosis (TB) is the most deadly infectious disease in the world. TB control relies on passive case findings and targeted treatment of latently infected individuals at high risk of disease progression. Tuberculin skin testing (TST) is conventionally used for detection of TB infection. Recently, blood assays measuring the release of IFN-gamma by TB-specific effector memory T cells have been developed to overcome TST limitations. Overall, IFN-gamma release assays are more specific than TST, more sensitive in detecting active TB and correlate better with TB exposure in immune-competent patients, at least in low-burden settings. There are three US FDA-approved assays commercially available: the ELISpot-based assay T-SPOT.TB (Oxford Immunotech, UK) and two ELISA-based formats, QuantiFERON TB Gold (QFT) and QFT-in tube (Cellestis, Australia). Recent international guidelines and consensus statements recommend the use of IFN-gamma release assays at different levels in TB management. However, conclusive evidence-based information targeting populations at high TB risk, including HIV-infected individuals, children and patient candidates for biotherapy with TNF-alpha blockers, are lacking. The aim of this review is to focus our attention on studies addressing the performance of commercial IFN-gamma release assays in clinical management of TB infection in these highly selected settings to provide a more comprehensive picture of the actual scenario and to identify areas to be investigated further.