Numerous hormones, growth factors and physiological processes cause a rise in cytosolic Ca2+, which is translated into meaningful cellular responses by interacting with a large number of Ca2(+)-binding proteins. The Ca2(+)-binding protein that is most pervasive in mediating these responses is calmodulin (CaM), which acts as a primary receptor for Ca2+ in all eukaryotic cells. In turn, Ca2+/CaM functions as an allosteric activator of a host of enzymatic proteins including a considerable number of protein kinases. The topic of this review is to discuss the physiological roles of a sub-set of these protein kinases which can function in cells as a Ca2+/CaM-dependent kinase signaling cascade. The cascade was originally believed to consist of a CaM kinase kinase that phosphorylates and activates one of two CaM kinases, CaMKI or CaMKIV. The unusual aspect of this cascade is that both the kinase kinase and the kinase require the binding of Ca2+/CaM for activation. More recently, one of the CaM kinase kinases has been found to activate another important enzyme, the AMP-dependent protein kinase so the concept of the CaM kinase cascade must be expanded. A CaM kinase cascade is important for many normal physiological processes that when misregulated can lead to a variety of disease states. These processes include: cell proliferation and apoptosis that may conspire in the genesis of cancer; neuronal growth and function related to brain development, synaptic plasticity as well as memory formation and maintenance; proper function of the immune system including the inflammatory response, activation of T lymphocytes and hematopoietic stem cell maintenance; and the central control of energy balance that, when altered, can lead to obesity and diabetes. Although the study of the CaM-dependent kinase cascades is still in its infancy continued analysis of the pathways regulated by these Ca2(+)-initiated signaling cascades holds considerable promise for the future of disease-related research.