Summary Simplifying and shortening treatment for drug-sensitive tuberculosis and providing new treatment options for drug-resistant tuberculosis constitute two principal goals in the development of novel drugs for tuberculosis. Demonstration of clinical efficacy in drug-sensitive tuberculosis is challenging, given high success rates for existing regimens, concerns about substituting an investigational agent for the most effective agents in a regimen and difficulties in determining the effect size of the components of a combination regimen. Large and prolonged studies would be needed either to show superiority over existing regimens or statistically defensible non-inferiority compared to existing regimens. In contrast, exploring efficacy of novel treatments in the setting of drug-resistant disease may present certain opportunities. In drug-resistant disease, the efficacy of existing regimens is comparatively poor, and companion drugs used to treat drug-resistant disease are weak or ineffective, enabling demonstration of the effect of the new drug. Other advantages of this approach, which has been used successfully in the development of antiretroviral agents, include the possibility of demonstrating drug efficacy using smaller studies, the possibility of accelerated approval based on a surrogate endpoint and the opportunity to address an urgent public health need. Experience with the activity and the safety of new agents in drug-resistant disease may provide a platform from which their indication can be broadened to include drug-sensitive disease.