Patients with chronic renal failure develop a "uremic" cardiomyopathy characterized by diastolic dysfunction, left ventricular hypertrophy, fibrosis, and systemic oxidant stress. Patients with chronic renal failure also are known to have increases in the circulating concentrations of endogenous cardiotonic steroids (also referred to as endogenous digitalis-like substances.) Endogenous cardiotonic steroids produce reactive oxygen species as part of the signal cascade induced by binding to the plasmalemmal Na/K-ATPase in patients, and this signal cascade appears capable of inducing several key pathophysiologic features of uremic cardiomyopathy. In addition, these patients develop both fibrosis and oxidant stress without a known mechanism. In this review we highlight data supporting the hypothesis that endogenous cardiotonic steroids are a key molecular component involved in the diastolic dysfunction, left ventricular hypertrophy, fibrosis, and systemic oxidant stress associated with chronic kidney disease.