Tuberculosis is still a major health problem worldwide. Although treatment regimens currently available can cure almost all tuberculosis drug susceptible cases, problems such as the length of treatment, the need for multidrug therapy, the emergence of drug resistance, HIV co-infection and persistent Mycobacterium tuberculosis bacilli, stress the need for new anti-tuberculosis drugs. Strategies to search for new anti-tuberculosis drugs involve: screening libraries of small molecules and natural products or the previous identification of targets crucial to the microorganism and the subsequent design of new molecules. Development of new drugs from known compounds having already shown safety and efficacy is an attractive strategy from the economical, pharmaceutical and clinical point of view. Several derivatives of known molecules and new compounds with different targets have been studied with promising preliminary results. Anti-tuberculosis compounds from natural sources have an enormous potential for the development of new drugs, which have shown not only antimicrobial activity per se but also inhibition of the mechanism of resistance (e.g. efflux pumps) or modulation of the immune response (e.g. macrophage stimulation). If these new drugs are going to have an impact in the treatment of the disease they should ideally be active not only against multiplying microorganisms but also against persistent or dormant bacilli. Due to the complexity of the pathology of M. tuberculosis it is unlikely that a single new drug will be enough. This review will discuss strategies for evaluating drug candidates, new targets, new compounds obtained from synthesis and natural sources, and clinical trials that are currently in progress.