Tuberculosis is a major global health problem. In the middle of the last century several laboratories identified, developed and synthesized several substances which were active against Mycobacterium tuberculosis, the causative agent of the disease. In the 1980s the standard oral treatment regimen was introduced with isoniazid, rifampicin, pyrazinamide, and ethambutol. In combination with the DOTS strategy it was possible treat TB within 6-8 months. But with the emergence of drug resistant strains, the formerly successful regiment became ineffective for MDR and XDR TB patients. Even more alarming, the rapidly increasing HIV epidemic also increases the number of HIV-related TB. Facing these facts, it became evident that novel strategies and antibiotics were needed to treat the new forms of TB. But over the last 60 years no novel TB drug was developed or even in the drug pipeline. But during the last ten years several novel substances have been developed to combat the deadly disease. For the first time in decades the TB drug pipeline is filled again with several promising compounds and many of them have reached Phase II and Phase III clinical trials. Several laboratories and companies all over the world currently are developing and evaluating these substances. This review presents novel substances, which were for the first time exclusively developed for TB such as bedaquilines, nitroimidazoles and the diamine SQ109. We also summarize the present knowledge about enzymes and biosynthesis pathways which offer potential targets for drug discovery against M. tuberculosis.