Mycobacterium tuberculosis (Mtb) infects human alveolar macrophages and relies on the inhibition of phagosome acidification and maturation. This is, in part, dependent on the disruption of host signaling networks within the macrophage. In recent years, Mtb-secreted protein- and lipid-phosphatases protein-tyrosine phosphatase A (PtpA), PtpB, and secreted acid phosphatase M (SapM) have been shown to contribute to Mtb pathogenicity. Here, we review the current knowledge on PtpA, PtpB, and SapM focusing on their ability to interfere with host functions. We further explore how these phosphatase-dependent host-pathogen interactions can be targeted for novel tuberculosis (TB) drug discovery and examine the ongoing development of inhibitors against these phosphatases.