Tuberculosis (TB) has played a central role in the history of biomedical science from Koch onwards. Research in the nineteenth and twentieth centuries yielded extremely valuable diagnostic, therapeutic and preventive tools for the control of TB. Following the development of shortcourse chemotherapy in the 1970s and 1980s, research into TB virtually evaporated. Despite the availability of an array of tools, TB control faltered, and the disease remains a major killer. The failure of the fruits of scientific research to control TB is a result of the shortcomings of the tools themselves as well the inadequate application of the tools in populations burdened by TB. A changing epidemiologic situation, with escalating rates of human immunodeficiency virus-related TB and the emergence of multidrug-resistant TB, further threatens global TB control. A robust TB research enterprise will be required to meet the global goals for controlling TB in the twentyfirst century. Basic research is needed to better understand its pathogenesis and immunology, and to identify targets for diagnostics, drugs and vaccines. Research into better biomedical tools to detect, treat and prevent TB is also a major priority, as all of the existing tools have important shortcomings. In addition, research into understanding how to apply both existing and new tools to control TB at the population level is urgently needed. Global funding for TB research, $483 million in 2007, is slowly growing but is far behind need. To meet the ambitious goals of the Global Plan to Stop TB and the Millennium Development Goals, a massive investment in research will be necessary.