The discovery that inositol lipids are fundamentally involved in cell signalling has been one of the most significant recent advances in cell biology. In particular, there is now evidence that certain products of polyphosphoinositide metabolism play second messenger roles in most cells. Inositol 1,4,5-trisphosphate and perhaps inositol 1,3,4,5-tetrakisphosphate bind to specific receptors and regulate Ca2+ release from, and movement between, intracellular stores. The synthesis of novel analogues of these second messengers is now providing clues to the structural requirements at such receptors as well as for molecules with stability towards metabolic enzymes. Stefan Nahorski and Barry Potter discuss these developments with a view to future pharmacological intervention at these sites.