It is clear that calcium ions are of considerable importance as a second messenger in insulin secretion. There is increasing evidence that calmodulin, a ubiquitous intracellular regulatory protein that mediates calcium-dependent processes, has a fundamental role in stimulus-secretion coupling. Calmodulin is present in the B cell and the secretion of insulin is inhibited by phenothiazines which bind to and inhibit the action of calmodulin. The evidence strongly suggests that phenothiazines influence insulin secretion by their effect on calmodulin which probably mediates calcium-dependent insulin release. It seems likely that calmodulin acts at several points in stimulus-secretion coupling, influencing cyclic nucleotide metabolism, protein phosphorylation and exocytosis. The discovery of calmodulin and the increasing clarification of its roles in cellular metabolism represent major steps towards our understanding of the mechanisms which influence the secretion of insulin.