There is compelling evidence that preconditioning occurs in humans. Experimental studies with potential clinical implications as well as clinical studies evaluating ischaemic, pharmacological and anaesthetic cardiac preconditioning in the perioperative setting are reviewed. These studies reveal promising results. However, there are conflicting reports on the efficacy of preconditioning in the diseased and aged myocardium. In addition, many anaesthetics and a significant number of perioperatively administered drugs affect the activity of cardiac sarcolemmal and mitochondrial KATP channels, the end-effectors of cardiac preconditioning, and thereby markedly modulate preconditioning effects in myocardial tissue. Although these modulatory effects on KATP channels have been investigated almost exclusively in laboratory investigations, they may have potential implications in clinical medicine. Important questions regarding the clinical utility and applicability of perioperative cardiac preconditioning remain unresolved and need more experimental work and randomized controlled clinical trials.