Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, and more effective strategies are required to control infection. The current vaccine, BCG, is only partially effective against TB, and drug-resistant strains of Mycobacterium tuberculosis are emerging at an alarming rate. The past decade has seen an explosion in the development of new TB candidates, with a handful of vaccines now in clinical trials. These vaccines take many forms (subunit, live attenuated, modified BCG) and are aimed at replacing BCG or enhancing BCG-induced immunity. The entry of new candidates into this TB vaccine ‘pipeline’ requires the rational design of novel vaccines effective against multiple stages of M. tuberculosis infection (i.e. target latent TB). Our approach has been to construct and assess live vaccines engineered to augment components of the immune response required for optimal anti-TB protective immunity. This has included the use of live attenuated M. tuberculosis strains lacking virulence factors that impact on the development of host immunity. Some of these vaccines have shown a marked ability to protect against infection in our pre-clinical models of TB. We have also used genetic screens to identify novel antigenic targets of M. tuberculosis for incorporation into new vaccines, and these studies have identified candidate antigens that protect against pulmonary M. tuberculosis infection in pre- and post-exposure animal models, and are strongly recognised by the immune system of TB patients. Our current focus is to prepare our most promising vaccines for assessment of efficacy against TB in human trials.