The classical role of the Na,K-ATPase is that of a primary active transporter that utilizes cell energy to establish and maintain transmembrane Na⁺ and K⁺ gradients to preserve cell osmotic stability, support cell excitability and drive secondary active transport. Recent studies have revealed that Na,K-ATPase located within cholesterol-containing lipid rafts serves as a receptor for cardiotonic steroids, including ouabain. Traditionally, ouabain was viewed as a toxin produced only in plants and it was used in relatively high concentrations to experimentally block the pumping action of the Na/K-ATPase. However, the new and unexpected role of the Na,K-ATPase as a signal transducer revealed a novel facet for ouabain in the regulation of a myriad of cell functions, including cell proliferation, hypertrophy, apoptosis, mobility and metabolism. The seminal discovery that ouabain is endogenously produced in mammals and circulates in plasma has fueled the interest in this endogenous molecule as a potentially important hormone in normal physiology and disease. In this article, we review the role of the Na/K-ATPase as an ion transporter in the kidney, the experimental evidence for ouabain as a circulating hormone, the function of the Na,K-ATPase as a signal transducer that mediates ouabain's effects and novel results for ouabain-induced Na,K-ATPase signaling in cystogenesis of autosomal dominant polycystic kidney disease (ADPKD).