Mycobacterium tuberculosis (Mtb), the main aetiological agent of tuberculosis (TB) in humans, is estimated to cause nearly two million deaths every year. Despite their huge therapeutic value, existing antitubercular drugs have several shortcomings, such as for instance the insurgence of drug resistance, which is mostly triggered by lack of compliance during the lengthy treatment. Novel and more effective drugs against Mtb acting on new molecular targets are therefore in demand in order to reduce treatment time and address the severe issue related to the progressive loss of antibiotic efficacy. Mtb encodes for two low molecular weight tyrosine specific phosphatases (MPtpA and MPtpB) that are crucially involved in Mtb pathogenesis. While MPtpA interferes with phagosome acidification blocking its maturation, MPtpB disrupts host signal transduction cascades, causing immune response subversion in the host. The important role played by both MPtpA and MPtpB in host–pathogen interaction makes them appealing targets for TB drug discovery. Here, we provide an exhaustive review of the current knowledge on MPtpA and MPtpB characterization and role in TB pathogenesis. In particular, special emphasis is placed on all class of inhibitors that have been developed and studied to date; their binding mode, design strategies, biological activities, main pharmacophore features as well as the efforts to overcome the poor druggability of their target are summarized in detail.