The major interventional trials of intensive insulin therapy in critically ill patients have reached divergent results. The present viewpoint article explores some of the potential reasons, including differences in monitoring technology and protocol design and performance, the occurrence of severe hypoglycemia and changes in the standard of care since publication of the landmark single-center trial. Recently published data detailing the deleterious effect of hypoglycemia are discussed, as is the emerging body of literature describing the important impact of glycemic variability on the risk of mortality in heterogeneous populations of acutely ill and severely ill patients. These new findings have important implications for the design of future interventional trials of intensive insulin therapy in the intensive care unit setting.