One of the key obstacles to TB control is the inadequacy of current drug therapies. Effective treatment of TB requires administration of multiple drugs for at least six months, a regimen that many patients are unwilling or unable to complete without close supervision. Prophylactic therapy of latent TB, when the patient has no clinical signs or symptoms, is especially problematic. Why is TB so difficult to cure? Our recent studies indicate that during later stages of infection mycobacteria may be in the stationary phase of growth. This could explain the recalcitrance of in vivo mycobacteria to conventional antimicrobials, which target cellular growth processes such as DNA replication and cell wall biogenesis. If correct, then development of “better, faster, cheaper” therapies for TB will hinge on the elucidation of bacterial pathways that are essential for nondividing persistence in the lungs.