Work is reviewed which provides evidence for the presence of a subsarcolemmal microdomain, in which the [Na+] is influenced by Na+ influx via the Na+ channel and the activity of the Na pump. The sarcolemma adjacent to this microdomain, which has been referred to as “Na+ fuzzy space,” appears to include Na-Ca exchangers, and thus alterations of [Na+] in this space may influence Ca2+ influx and efflux, and thus Ca2+ loading, more directly than do alterations of bulk cytoplasmic [Na+]. The degree of Ca2+ loading is an important determinant of contractility in heart muscle, and therefore alterations in fuzzy space [Na+] may be important in mediating the positive inotropic effects of Na pump inhibitors, such as digitalis, and the negative inotropic effects of Na+ channel blockers such as disopyramide. During ischemia, myocyte Ca2+ overload can contribute to ATP depletion by activation of Ca2+-dependent ATPases and by induction of the mitochondrial permeability transition, and thus is an important contributor to myocyte dysfunction and injury. Hypoxia associated with ischemia can induce Na+ influx via a persistent opening of the Na+ channel. It is likely that this Na+ influx elevates [Na+] in the fuzzy space, and thus increases Ca2+ influx via Na-Ca exchange, and increases Ca2+ loading. Inhibition of the persistent Na+ current with a resulting decrease in Ca2+ loading by drugs such as tetrodotoxin (TTX) and ranolazine may be a mechanism by which these agents produce a cardio-protective effect during ischemia.