Microglia, the primary immune cells in the central nervous system (CNS), are key to the maintenance of homeostasis in the brain parenchyma. In the intact brain, microglia continuously survey the microenvironment with ramified processes. Upon disease and/or damage, they rapidly convert into an amoeboid morphology, move toward the injury, and release cytokines to repair damage or clear debris. Purinergic signaling plays an important role in regulating microglial dynamics and immune responses. Specific purinergic receptors have been shown to participate in different aspects of microglial responses in the normal and diseased brains. In this review, we focus on the role of purinergic signaling-mediated microglial responses under physiological and pathological conditions.