We have achieved significant progress in understanding the central role of the insulin receptor in an increasingly complicated web of intracellular signal transduction leading to the ultimate biological actions of insulin on glucose, lipid, and other metabolic pathways. The excitement for the future lies not only in clarifying these pathways but also returning to whole-body physiology to readdress basic mechanisms of insulin action in known and novel insulin-sensitive tissues. Hopefully, these new techniques and new perspectives will bring us closer to understanding the pathophysiology of type 2 diabetes mellitus.