The waning of responses to cell-surface receptor activation during persistent stimulation with agonists (desensitization) is a feature common to many forms of transmembrane signalling. However, information is scarce regarding the regulatory processes that modulate the extensive group of receptors linked via phosphoinositidase C to the production of inositol 1,4,5-trisphosphate and 1,2-diacylglycerol. This situation is now beginning to change. Recent data indicate (1) that very rapid desensitization, possibly associated with receptor phosphorylation, regulates receptors linked to phosphoinositidase C, (2) that different receptors are desensitized to varying extents, (3) that receptor internalization can mediate desensitization at later times and (4) that signalling can be regulated at additional sites downstream of phosphoinositidase C. As Richard Wojcikiewicz and colleagues discuss here, these diverse regulatory events provide the means by which the breakdown of phosphoinositides and cellular responsiveness to their products are controlled during cell stimulation.