Intracellular acidification may be the initial stimulus for a cascade of events contributing to intracellular calcium overload. Ischaemia results in the accumulation of lactate and other proton donors causing intracellular acidification. During reperfusion the activity of the Na+/H+ exchanger recovers, allowing extrusion of protons at the expense of increases in intracellular sodium. The rise in intracellular sodium decreases the gradient required for sodium calcium exchange, resulting in accumulation of intracellular calcium. These data are in keeping with the pathophysiological model that the Na+/H+ exchanger is an important part of a cascade leading from intracellular acidosis to intracellular sodium loading followed by calcium overload. From this model we predicted that amiloride would be antiarrhythmic. In 1988, we reported that low concentration of amiloride (0.1–0.3 μM) suppresses the induction of sustained ventricular tachyarrhythmias in dogs late following infarction. Amiloride suppressed inducible ventricular tachycardia in approximately 50% of the animals. In an extension of this work we assessed the efficacy of amiloride in suppressing inducible ventricular tachycardia in humans who presented with symptomatic ventricular tachycardia. In that study, amiloride manifested antiarrhythmic activity, but not to the degree that was observed in our dog model. Six of 31 patients (19%) had complete suppression of induced ventricular tachycardia. In an extension of this work, we assessed in our in vivo dog model which of the pharmacological effects of amiloride were associated with antiarrhythmic efficacy. The major new findings of that in vivo study were: (1) the possibility that isolated blockade of the Na+/Ca2+ exchanger or the Na+/H+ exchanger produces the antiarrhythmic efficacy of amiloride was excluded, but simultaneous blockade of the Na+/Ca+ and the Na+/H+ ion exchangers by the congeners in combination had antiarrhythmic efficacy similar to amiloride but did not prolong border zone refractoriness; (2) increases in magnesium or potassium did not mediate antiarrhythmic activity in this model; (3) barium produced antiarrhythmic and electrophysiological effects similar to amiloride; (4) the possibility that block of ICa is responsible for the antiarrhythmic activity of amiloride was excluded. The most likely mechanism of the antiarrhythmic activity of amiloride relates to the enhanced antiarrhythmic activity that was observed with the two selective amiloride congeners in combination. This activity probably reflects the addition of Na+/Ca+ and Na+/H+ exchanger blocking effects. The results of this study also suggest that the antiarrhythmic activity of amiloride may at least in part be related to Ik1 blockade by amiloride. In conclusion, blockade of the sodium-proton and the sodium-calcium exchangers has therapeutic promise. However, broader based studies with greater numbers of patients using drug treatments with more selective effects appear to be necessary before these agents can be considered as first line therapy to preserve myocardial function or as antiarrhythmic therapy.