Na,K-ATPase is the driving force for renal Na+ reabsorption and is thus critically implicated in the control of extracellular volume and blood pressure. This review focuses on most recent advances in the elucidation of intrinsic structural features that are important for Na,K-ATPase function and in the identification of regulatory mechanisms that are implicated in the modulation of Na,K-ATPase activity in the kidney under physiological or pathophysiological conditions.