Mycobacterium tuberculosis is the most successful human pathogen due to its ability to challenge the innate immune system and survive in the infected host for a lifetime. Although tuberculosis (TB) is a curable disease, severe multidrug resistance to traditional antibiotics has caused a resurgence of the infection worldwide. The secreted phosphatases MptpA and MptpB are key virulence factors that play important roles in survival of M. tuberculosis during macrophage infection. These enzymes are therefore attractive alternative targets for chemotherapy. In this review we analyze the structural features that characterize these two phosphatases and differentiate them from human homologs. Their structural peculiarities are important for drug-design considerations and the future development of selective inhibitors. We describe the recent efforts in developing specific, selective and cell-active inhibitors of MptpA and MptpB, and discuss their potential applications as alternative treatments of TB.