Intracellular bacterial pathogens such as Mycobacterium tuberculosis are remarkably adept at surviving within a host, employing a variety of mechanisms to counteract host defenses and establish a protected niche. Constant surveying of the environment is key for pathogenic mycobacteria to discern their immediate location and coordinate the expression of genes necessary for adaptation. Two‐component systems efficiently perform this role, typically comprised of a transmembrane sensor kinase and a cytoplasmic response regulator. In this review, we describe the role of two‐component systems in bacterial pathogenesis, focusing predominantly on the role of sensor kinases of M. tuberculosis. We highlight important features of sensor kinases in mycobacterial infection, discuss ways in which these signaling proteins sense and respond to environments, and how this is attuned to their intracellular lifestyle. Finally, we discuss recent studies which have identified and characterized inhibitors of two‐component sensor kinases toward establishing a new strategy in anti‐mycobacterial therapy.

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