Insulin has been used in the treatment of patients undergoing cardiac surgery or suffering from acute myocardial infarction. Most of these investigations have demonstrated that the metabolic cocktail consisting of glucose-insulin-potassium (GIK) improves recovery of function and outcome after cardiac surgery and substantially reduces mortality of patients with acute myocardial infarction. There is also evidence suggesting that insulin is not effective under these conditions, as demonstrated in a recent large randomized trial in cardiac surgery. It is therefore not surprising that insulin or GIK is not used routinely in clinical practice. Many hypotheses have been advanced to explain the effects of insulin and GIK but none of them has enjoyed convincing support. In cardiac surgery the many different application protocols described make it difficult to compare the results. The application of GIK after cardiac surgery may be complicated by severe disturbances in glucose or potassium homeostasis. In this article we review the literature in this field, addressing the areas of controversy. We discuss the different mechanisms suggested and we propose potential solutions. We conclude that a multifactorial mechanism is likely to explain the effects of insulin or GIK after ischemia and we propose that in a practical sense the application of high-dose insulin during reperfusion, utilizing a newly described, direct nonmetabolic effect, is a convincing concept. We will further demonstrate our clinical experience in establishing a protocol for putting this concept into clinical practice.