The widespread role of calmodulin in mediating Ca2+-dependent activities raises the possibility that calmodulin antagonists might be used effectively to alter cellular function. Current progress toward the development of calmodulin antagonists of suitable selectivity and specificity is considered in this review. Phenothiazines and other antipsychotic agents, including trifluoperazine, are among the most potent antagonists of calmodulin actions. Their antagonism of calmodulin function correlates with binding to calmodulin, probably at a hydrophobic region induced by Ca2+. Binding to this region is not stereospecific nor restricted to antipsychotic agents, as a wide range of hydrophobic molecules interact similarly and inhibit calmodulin activity. Trifluoperazine is not a specific antagonist of calmodulin, as it interacts with other Ca2+-binding proteins and also inhibits many lipid-dependent enzyme activities, including a widely distributed Ca2+ and phospholipid-dependent protein kinase. New data is presented showing that trifluoperazine, in addition to its binding to calmodulin, binds to the activated states of calmodulin-sensitive enzymes, in particular erythrocyte Ca2+- and Mg2+-stimulated ATPase. The implications of the lack of selectivity of presently available "calmodulin antagonists" are assessed.