Many patients with type 2 diabetes go on to require insulin therapy to achieve adequate control. A need remains to develop new classes of oral hypoglycemic agents to complement those already in use. A useful target is the inappropriately elevated endogenous glucose production present in patients with type 2 diabetes. This review discusses mechanisms of increased glucose production and possible strategies and targets for its suppression. Several approaches are being investigated, including inhibitors of glycogenolysis and gluconeogenesis, inhibitors of stimulatory hormones or their receptors, metabolic modulators, and agents that alter gene expression. There is a high probability that one of these approaches will soon result in a safe and effective inhibitor of glucose production.