Prior to the introduction of modern drugs like angiotensin converting enzyme inhibitors and β-adrenergic receptor antagonists, the cardiac glycoside ouabain (referred to as g-Strophanthin in German) has routinely been used in treatment of heart diseases. Decades of practical use indicate benefits in prevention and treatment of acute heart attacks. Prophylactic and therapeutic use of ouabain was recommended in insufficiencies of the left ventricle. This clinical experience disappeared in time, yet there is mounting evidence that supports a re-evaluation of ouabain in the treatment of heart disease. In 1991 ouabain was identified as an endogenous hormone. This discovery has lead to an intense re-examination of the drug, its physiological functions and its mode of action. New research illustrates the uniqueness of ouabain and thus confirms the extensive clinical experiences. Moreover, a recent study confirmed the long-known clinical observation that ouabain has an inhibitory effect on cardiotoxicity induced by other digitalis glycosides. Mechanistic studies have validated the clinical experience that ouabain is different from other cardiac glycosides. In contrast to digitalis glycosides ouabain modulates the metabolism of the heart; it stimulates substrate utilization of the myocardium, removes lactate accumulated during heart diseases, and reduces the amount of fatty acids in the blood. This profile makes ouabain a valuable prototype for new drugs, which offer new approaches for causal treatment of heart diseases. Clinical studies with ouabain that correspond to current standards are warranted.