The number of G proteins identified by molecular cloning exceeds the number of known G protein functions. Here we show that a cell can possess multiple G proteins that carry out a similar function, the activation of phospholipase C, but couple selectively to different receptors, which are endogenous to the cell or introduced by DNA transfection. These G proteins (termed Gp) can be distinguished by their sensitivity to pertussis toxin. The assignment of a given Gp pathway to specific receptors is confirmed by the additivity relationships of the PI hydrolysis response mediated by the different receptors. Significantly different amounts of PI hydrolysis are activated through each Gp pathway, suggesting that Gp proteins also differ in their coupling to phospholipase C. These results indicate that distinct Gp pathways in a given cell exist to couple different receptors to PI hydrolysis selectively, and may specify the nature of the cellular response to different receptors by determining the magnitude of PI hydrolysis.