The Na⁺/K⁺-ATPase is a transmembrane protein acting as an electrogenic Na⁺ and K⁺ transporter in the plasma membrane of all mammalian cells.  Although the Na⁺/K⁺-ATPase was first discovered in neuronal tissue, its function has been more extensively characterized in cardiac and renal tissues, and the Na⁺/K⁺-ATPase has emerged as a novel drug target in these systems. This review will focus on the function and dysfunction of the plasma membrane Na⁺/K⁺-ATPase in the context of neuronal diseases. More specifically, we will outline the structure, function, and regulation of the Na⁺/K⁺-ATPase under normal as well as hypoxic/ischemic conditions. We will review recent evidence on the relationship between the Na⁺/K⁺-ATPase and K⁺ homeostasis in neuronal apoptosis, outline the emerging role of ouabain and other Na⁺/K⁺-ATPase inhibitors as endogenous hormones which activate specific signal transduction cascades by binding to the Na⁺/K⁺-ATPase, and evaluate the impact of these signal transduction functions on the role of Na⁺/K⁺-ATPase in CNS diseases.