Elective temporary cardiac arrest (cardioplegia) is often required during cardiac surgery. In the 1970 s, the development of hyperkalaemic cardioplegic solutions revolutionised cardiac surgery by offering effective chemically-induced cardiac arrest and myocardial protection during global ischaemia. Despite remaining the most widely-used cardioplegic technique, hyperkalaemia can have detrimental effects due to the Na and Ca loading of the cardiac cell induced by depolarisation of the cell membrane. Efforts over the last two decades to establish better cardioplegic agents have mainly remained limited to animal experiments. The failure of these approaches to progress to clinical trials may be due to a lack of clear criteria that a cardioplegic agent should meet at a cellular level and, more importantly, at a system level. In this review we attempt to define the criteria for the optimal cardioplegic agent. We also assess the suitability and clinical potential of previously-studied cardioplegic agents and suggest cellular targets, particularly those involved in cardiac excitation-contraction coupling, that may prove to be attractive options for the development of new cardioplegic drugs. Finally, we propose a multicellular target approach using a combination of pharmacological agents in order to offer better cardioplegic solutions.