Hyper- and hypoglycemia are associated with increased morbidity and mortality of critically ill patients, following a J-shaped curve, but whether this association is causal remained unclear. Early randomized-controlled studies compared insulin infusion targeting "age-normal" blood glucose levels, labeled intensive insulin therapy, with an approach that considered hyperglycemia as a beneficial adaptation and hence left it largely untreated. These studies found clear benefits with targeting and maintaining normoglycemia. A recent large multicenter study, NICE-SUGAR, compared a similar "age-normal" with an intermediate glucose target and found the intermediate target safer. The methodological differences between the repeat studies, most specifically NICE-SUGAR, and the original proof-of-concept studies, are systematically analyzed in this lecture, in order to address the at first sight inconsistent results. In addition, the lecture will cover the important data on the underlying mechanisms that play a role in explaining the adverse effects of acute hyperglycemia in the critically ill.