Obesity is associated with aberrant sodium/potassium-adenosine triphosphatase, (Na+/K+-ATPase) activity, apparently linked to hyperglycemic-hyperinsulinemia, which may repress or inactivate the enzyme. Reduction of Na+/K+-ATPase activity in cardiac tissue induces myocyte death and cardiac dysfunction leading to the development of myocardial dilation in animal models; this has been also documented in patients with heart failure. During several pathological situations (cardiac insufficiency, heart failure) and experimental models (obesity), the heart becomes more sensitive to the effect of cardiac glycosides, due to a decrease in Na+/K+-ATPase levels. The primary female sex steroid, estradiol has long been recognized to be important in a wide variety of physiological processes. Numerous studies including ours show that estradiol is one of the major factors controlling Na+/K+-ATPase activity/expression in the cardiovascular system. However, the effects of estradiol on Na+/K+-ATPase both in normal and in pathological conditions, such as obesity remain unclear. Increasing our understanding of the molecular mechanisms by which estradiol mediates its effects on Na+/K+-ATPase function, may help to develop new strategies for the treatment of cardiovascular diseases. Here we discuss the latest data from animal and clinical studies that examine how pathophysiological conditions such as obesity and the action of estradiol regulate Na+/K+-ATPase activity.