Bacillus Calmette-Guérin (BCG) is the only preventive treatment for tuberculosis in humans, but this live vaccine confers variable protection against pulmonary tuberculosis in adults. Advances in the understanding of Mycobacterium tuberculosis immunopathogenesis have renewed hopes of developing new prophylactic vaccines conferring better protection than BCG. The authors describe here state-of-the-art attenuated live vaccines based on inactivation of the phoP gene, a transcriptional regulator of key virulence networks in M. tuberculosis. Recent preclinical testing of live vaccines based on phoP inactivation has demonstrated proof of concept, with a high degree of attenuation and protection against disease observed in various animal models. These results demonstrate that phoP mutants are promising new live vaccines for tuberculosis prevention. The steps that now need to be followed, to take these live vaccines towards clinical trials, are also reviewed, together with the potential of these vaccines to replace BCG.