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 vaccine and drug candidates, with a number now in clinical trials. 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). We have used genetic screens to identify novel antigenic targets of M. tuberculosis for incorporation into new vaccines. 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. We have also undertaken a program of drug discovery by screening natural product libraries for antimycobacterial activity. We identified samples from marine organisms with exceptionally potent activity against drug-susceptible and drug-resistant strains of M. tuberculosis. These samples were non-toxic against human cell lines, could work in synergy with existing TB drugs, and were able to inhibit intracellular growth of M. tuberculosis. Our current focus is to prepare our most promising vaccines and drugs for assessment of efficacy against TB in human trials.