Tuberculosis (TB) remains a major challenge to global public health in the 21st century. In 2007, there were an estimated 9.27 million new cases and 1.3 million deaths among HIV-negative patients with TB. The HIV-associated TB epidemic, drug-resistant disease, the need for better diagnostic assays and the limited efficacy of Bacille Calmette-Guerin vaccination are four important obstacles to further progress in global TB control. In this brief review, we provide a focused update on these four key areas of TB research.