When heart muscle becomes ischaemic its reserves of adenosine triphosphate (ATP) and creatine phosphate (CP) are rapidly depleted. As a result there is a rise in organic phosphate (P i ), and the energy-dependent mechanisms which normally operate to maintain intracellular ionic homeostasis fail. Consequently intracellular Na $ rises and Ca 2$ overload occurs. Mitochondria that are exposed to excess Ca 2$ rephosphorylate ADP only slowly, so that when reoxygenation occurs they are unable to generate ATP at a rate which is sufficiently fast to prevent the occurrence of a massive influx of Ca 2$ , with a consequent loss of cell liability. Agents which might be expected to reduce the rate at which the myocardium utilizes A TP include the Ca 2$ and β-adrenoceptor antagonists. Theoretically, therefore, these agents should protect heart muscle against the deleterious effects of ischaemia and reperfusion. To test this hypothesis rabbits have been pretreated with a series of Ca 2$ or β-adrenoceptor antagonists, including nifedipine, verapamil, propranolol and oxprenolol. The hearts have then been isolated, perfused and made ischaemic at 37 C. The protection afforded by these drugs has been assessed in terms of their ability to protect the A TP generating capacity of the mitochondria and to prevent Ca 2$ overload. Recovery of mechanical function during reperfusion was also monitored. In a second series of experiments, the drugs were added to the coronary perfusion line either at the start of the perfusion, immediately prior to the start of the ischaemic episode, at the start of reperfusion or 10 min after starting reperfusion. The results obtained from these experiments will be discussed in terms of: (1) the ability of the drugs to protect against the deleterious effects of ischaemia and reperfusion: (2) the critical timing of the drug administration: (3) the role of Ca 2$ .