Mycobacterium tuberculosis remains one of the world’s most deadly bacteria resulting in infection in nearly a third of the global population and millions of deaths per year. Clinically, tuberculosis is highly variable. Even within one patient, sites of infection can have different outcomes. One of the critical players during infection is the macrophage, an innate immune cell that is among the first to encounter M. tuberculosis. We take the viewpoint of both the bacterium and the macrophage to understand what factors drive the outcome of infection using new technologies and classical approaches. Our ultimate goal is to manipulate these cells therapeutically to fight tuberculosis infection.