Evidence suggest that histamine is required for the diabetogenic agent streptozotocin to exert its toxicity on islet beta-cells. The effects of histamine and L-histidine on the replication and long-term insulin secretion by pancreatic beta-cells were investigated. L-histidine dose-dependently increased insulin secretion and suppressed DNA synthesis without affecting the islet insulin content. Histamine suppressed beta-cell replication but failed to affect the islet content or secretion of insulin. Depletion of islet histamine contents by the specific and irreversible inhibitor of L-histidine decarboxylase, alpha-fluoromethyl-[S] histidine increased islet insulin content but failed to influence the rate of insulin secretion. The present results suggest that exogenously added L-histidine, but not histamine, stimulates insulin secretion whereas both substances suppress beta-cell growth. Endogenously formed histamine may have different roles in beta-cell function than exogenously delivered histamine, the latter likely acting through specific cell surface receptors.