Tuberculosis (TB) has been the biggest killer in the human history; currently, M. tuberculosis (Mtb) kills nearly 2 million people each year around the world. The high prevalence of TB obliges the identification of new therapeutic targets and the development of active anti-TB vaccines useful for the control of multidrug resistance and latent TB infections. Membrane proteins have been lately suggested as key targets for bacterial viability. Recent studies have shown that mycobacteria P-type ATPases may have critical roles in ion homeostasis and in the response of mycobacteria to toxic substances in the intraphagosomal environment. In this review, we draw together genomic, transcriptomic and structural aspects of P-type ATPases that are relevant during active and latent M. tuberculosis infection, which can be useful to figure out their potential as drug targets and their possible role in the design of new anti-TB attenuated vaccines.