Prior to consideration of the effects of digitalis compounds on ionic exchange the basic mechanisms of active Na+and K+transport are discussed. It is generally accepted that digitalis is a specific inhibitor of the Na+-K+activated ATPase located primarily in the sarcolemmal membrane. Present evidence supports the concept that positive inotropic effects of digitalis are not seen unless evidence of inhibition of the enzyme and, therefore, of the “Na pump’ leads to a small increase of intracellular Na+. This leads to augmented activity of a Na+transport system which is coupled, not to K+, but to Ca+ +. Evidence for the existence of Na+-Ca+ +coupling at excitable membranes is accumulating, and this is reviewed. The possibility that administration of digitalis, through its inhibition of the Na+-K+coupled system produces an increase in Na+- Ca+ +coupled transport and thereby an increase of influx of Ca+ +to the myofilaments is discussed and is presented as a possible basis for the mechanism of digitalis action. The toxic electrophysiologic effects of digitalis are discussed in terms of the effects on K+exchange induced by the drug.