The Mycobacterium tuberculosis PhoPR two-component system is essential for virulence in animal models of tuberculosis. Recent articles have shown that among the reasons for the attenuation of the M. tuberculosis H37Ra strain is a mutation in the phoP gene that prevents the secretion of proteins that are important for virulence. There is a need for new anti-tubercular therapies because of the emergence of multi-drug-resistant M. tuberculosis strains and also the variable efficacy of the currently used bacille Calmette-Guérin vaccine. Because of its major role in M. tuberculosis pathogenicity, PhoP is a potential target candidate. This review summarizes our understanding of PhoPR's role in virulence and discusses areas in which our knowledge is limited.