The purinergic receptor, P2X7, has recently emerged as an important component of the innate immune response against microbial infections. Ligation of P2X7 by ATP can stimulate inflammasome activation and secretion of proinflammatory cytokines, but it can also lead directly to killing of intracellular pathogens in infected macrophages and epithelial cells. Thus, while some intracellular pathogens evade host defense responses by modulating with membrane trafficking or cell signaling in the infected cells, the host cells have also developed mechanisms for inhibiting infection. This review will focus on the effects of P2X7 on control of infection by intracellular pathogens, microbial virulence factors that interfere with P2X7 activity, and recent evidence linking polymorphisms in human P2X7 with susceptibility to infection.