Targeted testing and treatment of individuals with latent tuberculosis infection at increased risk of progression to active disease is a key element of tuberculosis control. This strategy is limited by the poor specificity of the tuberculin skin test in populations vaccinated with bacille Calmette-Guérin and its low sensitivity in immunosuppressed persons, who are at highest risk of progression. Two blood tests (T-SPOT.TB and QuantiFERON-TB Gold), based on detection of IFN-gamma released by T cells in response to M. tuberculosis-specific antigens, may offer an improvement on the skin test. However, validation is challenging due to the lack of a diagnostic gold standard. This critical appraisal of published evidence summarizes the diagnostic accuracy of the new tests. The blood tests have operational advantages over the skin test because no return visit is required, results are available by the next day, and repeated testing does not cause boosting. Both tests are significantly more specific than the skin test in populations vaccinated with bacille Calmette-Guérin. The data suggest that T-SPOT.TB may be more sensitive than the skin test. Data in groups at high risk of progression to disease are scarce, and more research is needed in these populations, but it is clear that T-SPOT.TB performs better than the skin test in young children and HIV-infected people with active tuberculosis. Incorporation of these tests into programs for targeted testing of latent tuberculosis infection will reduce false-positive and false-negative results inherent in tuberculin testing, equipping clinicians with more accurate tools for tuberculosis control and elimination in the 21st century.