Microglial activation by purines and pyrimidines is reviewed, with emphasis on the actions of adenosine 5′-triphosphate (ATP) on chemotaxis or releases of plasminogen and cytokines from microglia. ATP activates microglia, causing morphological changes with membrane ruffling. Activated microglia exhibit chemotaxis to ATP. Microglia stimulated by a low concentration of ATP (∼30–50 μM) rapidly release plasminogen (within 5–10 min), which may protect neurons. Microglia stimulated by a higher concentration of ATP release tumor necrosis factor-α (TNF-α), 2–3 h after the stimulation and interleukin-6 (IL-6), 6 h after the stimulation. It is reported that TNF-α stimulation causes an increase in the expression of IL-6 receptor mRNA and expression in neuronal cells (März et al. 1996. Brain Res 706:71–79). After binding with gp130, the IL-6 receptor matures and can accept IL-6 molecules. It is speculated that neurons may require several hours to prepare for the full reception of IL-6, which induces a more efficient protective effect by IL-6 after stimulation with TNF-α. After neurons are ready to accept IL-6 fully, microglia release IL-6 to neurons. Stronger and longer stimulation by ATP may change the function of microglia and cause cell death. The conditions evoking the heavy stimulation would result from serious injury. Activated microglia act as scavenger cells that induce apoptosis in damaged neurons by releasing toxic factors, including NO, and removing dead cells, their remnants, or dangerous debris by phagocytosis. These actions lead to a suitable environment for tissue repair and neural regeneration. The fate of neurons may therefore be regulated in part by ATP through the activation of microglia. GLIA 40:156–163, 2002. © 2002 Wiley-Liss, Inc.