Adrenocorticotropic hormone (ACTH) increases cAMP and cGMP concentrations in both adrenal and lymphoid cells, and requires extracellular Ca to have biological activity. The requirement for Ca has been difficult to characterize in terms of the channel identity and whether the committing step for steroidogenesis in the adrenal cells requires Ca. In lymphocytes, ACTH has a biphasic effect on functions such as proliferation and immunoglobin secretion. Current information is consistent with suppressive effects of high ACTH concentrations being mediated by cAMP. Stimulatory effects of ACTH concentrations are hypothesized to be mediated by Ca uptake. This review will discuss the localization of Ca signals to discrete domains within cells and the receptor- and tissue-specificity of their subcellular distribution. Considering the diversity of possible mechanisms, a hypothesis for the role of ACTH-stimulated Ca uptake during mitogen activation of T-cell lymphocytes will be presented.