PURPOSE OF REVIEW: There is evidence that maintaining a normal glycemia level in critically ill patients has beneficial effects on outcome. Strategies aimed at lowering glycemia are based on the understanding of mechanisms regulating glucose metabolism. RECENT FINDINGS: Activation of AMP protein kinase in skeletal muscle and in the liver leads to a reduction in glucose production, a stimulation of glucose uptake, and a lowering of glycemia. These mechanisms appear to be activated during exercise, or by the endogenous adipokine adiponectin. Alterations in adiponectin concentrations during critical illness may thus play a role in the metabolic stress responses. In addition, AMP-activated protein kinase is the target for drugs (metformin, thazolidinediones), which may be of interest in the intensive care unit. Besides insulin, plasma glucose concentrations may be lowered by hypocaloric feeding, or by feeding 'diabetic' formula with low glucose content and supplemented with fructose. Whether such approaches lead to beneficial effects comparable to those observed with insulin remains to be established. SUMMARY: Recent findings regarding the molecular mechanisms underlying glucose transport and metabolism are summarized, and potential strategies other than insulin are outlined which may contribute to lowering glycemia in critically ill patients.