The neuropeptide substance P, the venom peptide mastoparan and the synthetic polyamine compound 48/80 activate rat peritoneal mast cells, leading to rapid histamine release by exocytosis. Although these effects are inhibited by pertussis toxin and involve a transient increase in IP3, no selective membrane receptors have been identified. However, it has recently been shown that these compounds activate G proteins in vitro. Here Yves Landry and colleagues discuss the proposal that direct activation of G protein is the physiological mechanism of action of substance P on rat peritoneal mast cells, this mechanism being mimicked by mastoparan and 48/80, and possibly by other cationic amphiphilic peptides such as kinins. These compounds might be of help in defining the interaction between membrane receptors and G proteins.