Co-workers and I examined the early events in the interaction of rat peritoneal mast cells with a number of noncytotoxic mast cell stimuli. These studies demonstrated that an interaction limited to the cytoplasmic membrane is sufficient to induce a secretory mast cell response. Additional experiments suggested that a continued interaction between the stimulus and the membrane receptor is required for maintenance of the secretory response. We have provided evidence to support the concept that different mast cell activators interact with different receptors on the cell membrane and initiate distinct biochemical pathways leading to secretion. Finally, we have shown that pretreatment of mast cells with concentrations of a stimulus that, by themselves, are incapable of initiating a secretory response can profoundly affect the ability of mast cells to respond fully to a subsequent challenge with an optional concentration of stimulus.