AbstractMicroglia are sensitive to environmental changes and are immediately transformed into several phenotypes. For such dynamic “modal shifts”, purinergic receptors have central roles. When microglia sense ATP/ADP leaked from injured cells by P2Y12 receptors, they are transformed into a moving phenotype, showing process extension and migration toward the injured sites. Microglia upregulate adenosine A2A receptors, by which they retract the processes showing an amoeboid‐shaped, activated phenotype. Microglia also upregulate P2Y6 receptors, and if they meet UDP leaked from dead cells, microglia start to engulf and eat the dead cells as a phagocytic phenotype. The P2Y12 receptor‐mediated responses are modulated by other P2 or P1 receptors. In contrast, the P2Y6 receptor‐mediated responses were not influenced by P2Y12 receptors and vice versa. Microglia appear to use purinergic signals either cooperatively or distinctively to cause their modal shifts. © 2012 Wiley Periodicals, Inc.