Abstract In 1975, Michell first proposed that activation of phosphatidylinositol turnover provided a direct link between surface receptors and membrane Ca gates. Subsequently, a number of laboratories have begun to re-investigate this phenomenon first described by Hokin and Hokin some twenty years earlier. As would be expected, some new hypothesis have emerged, most being extensions or revisions of Michell's original concept. Despite difficulties in obtaining direct proof, indirect evidence suggests that the plasma membrane is the primary locus of receptor-activated phosphatidylinositol turnover, at least for phosphatidylinositol breakdown and phosphatidic acid synthesis. The presence or absence of Na + can markedly affect labelling of phosphatidylinositol by radioactive precursors but there is no compelling evidence that the initial events are mediated by Na +. Prostaglandins are apparently formed in some tissues on receptor activation, but in most instances the evidence suggests that these compounds are not obligatory intermediates in tissues that show the phosphatidylinositol effect. Several laboratories have obtained evidence that phosphatidic acid newly synthesized following phosphatidylinositol breakdown, may function as an endogenous Ca ionophore under neurohumoral control.