In this brief review we discuss some aspects of the Na+ pump and its roles in mediating the effects of ouabain and endogenous ouabain (EO): i) in regulating the cytosolic Ca2+ concentration ([Ca2+]CYT) via Na/Ca exchange (NCX), and ii) in activating a number of protein kinase (PK) signaling cascades that control a myriad of cell functions. Importantly, [Ca2+]CYT and the other signaling pathways intersect at numerous points because of the influence of Ca2+ and calmodulin in modulating some steps in those other pathways. While both mechanisms operate in virtually all cells and tissues, this article focuses primarily on their functions in the cardiovascular system, the central nervous system (CNS) and the kidneys.