Phosphoinositides are minor membrane lipids involved in many cellular signaling processes. The addition or removal of phosphates on phosphoinositides depends on the interplay of specific lipid kinases and phosphatases. P2X receptors are cation channels that are gated by extracellular ATP. They play multiple and important physiological roles in vertebrates, ranging from pain sensation and control of smooth muscle contraction to cytokine release and immune cell death. In this article, we review recent studies that have identified phosphoinositides as critical modulators of P2X receptor function.