New agents are being developed to address the underlying endocrinopathies and metabolic disturbances of type 2 diabetes. Stimulants of the nuclear peroxisome proliferator-activated receptor γ (PPARγ) are being identified to selectively improve insulin actions, and dual agonists of PPARγ and PPARα are being evaluated for enhanced control of hyperglycemia and dyslipidemia. Novel activators of insulin receptor phosphorylation and inhibitors of receptor dephosphorylation are offering encouraging leads for new agents. Analogues of glucagon-like peptide-l that increase glucose-induced insulin secretion may additionally increase ß-cell neogenesis from progenitor duct cells. The amylin analogue pramlintide, which suppresses glucagon secretion and reduces weight, is advancing in clinical trial. Direct stimulants of glucose utilization and partial inhibitors of gluconeogenesis are providing useful new drug templates. Thus, new pharmacologic approaches are emerging to treat the multiple lesions of type 2 diabetes.