Tuberculosis (TB) continues to be one of the greatest challenges in the global public health arena. Current therapeutic agents against TB are old and inadequate, particularly in the face of many new challenges. Multidrug-resistant TB (MDR-TB) has become prevalent in many parts of the world and extensively drug-resistant TB (XDR-TB) is rapidly emerging. There are few or essentially no effective drugs available to treat these drug-resistant forms of TB. TB and human immunodeficiency virus (HIV) coinfection has become another major problem in areas with high prevalence of HIV infection. Simultaneous treatment of TB and HIV is difficult due to the severe drug-drug interactions between the first-line rifamycin-containing TB therapy and antiretroviral agents. However, there have been some encouraging developments in TB drug research and development within the past decade. At present there are 6 compounds, including 3 novel agents, in late stages of clinical development. There are even larger numbers of compounds and projects in the TB drug pipeline at the discovery stage and in early stages of clinical development, mainly targeting treatment shortening and drug resistance. Despite these encouraging developments, the current TB drug pipeline is not sufficient to address the multitude of challenges inherent in the current standard of TB therapy. A stronger TB drug pipeline and a new paradigm for the development of novel TB drug combinations are needed.