IL-1beta is one of the most potent proinflammatory cytokines. It is primarily released from activated microglia in the brain, and is also implicated in the induction and progression of pathogenesis in various neurodegenerative disorders. Therefore, to clarify the regulatory or modulatory mechanisms for maturation and release of IL-1beta from microglia may provide therapeutic clues for neuroinflammatory/neurodegenerative diseases. IL-1beta lacks a secretory signal sequence, and thus is not transported through the classical cndoplasmic reticulum/ Golgi-mediated pathway. Although the mechanisms for the release of mature IL-1beta still remain controversial, emerging evidence suggests the pivotal roles of the P2X7 receptor (P2X7R), one of the ionotropic P2X receptors for extracellular ATP, in the release of this cytokine. Here, we review the current studies regarding the modulatory mechanisms of P2X7R-dependent maturation and the release of IL-1beta from microglial cells, focusing on the novel roles of lysophospholipids in this process.