Calmodulin, a ubiquitous calcium-binding protein, has recently been shown to play an important role in cellular proliferation. The calmodulin inhibitors melittin, trifluoperazine, and chlorpromazine inhibited the growth and clonogenicity of human and murine leukemic cells, and their potency reflected their activity as inhibitors of calmodulin. Melittin, which is a far more potent inhibitor of calmodulin activity, was also a more potent inhibitor of cell growth and clonogenicity. The less active phenothiazine metabolite, chlorpromazine sulfoxide, had much less potent cytotoxic activity.