T2D develops in response to overnutriton and lack of physical activity in subjects that have underlying genetic and acquired predispositions to both insulin resistance (and/or hyperinsulinemia) and β cell dysfunction. Over time, islet β cell compensation for the insulin resistance fails, resulting in a progressive decline in β cell function. As a consequence, subjects progress from normal glucose tolerance (NGT) to IGT and finally to established T2D. Even after diagnosis of T2D, β cell function continues to worsen such that subjects progress from needing changes in diet/exercise only to requiring oral hypoglycemic agents and eventually insulin for achievement of adequate glycemic control. Future therapies will be directed not only to achievement of euglycemia, but also changing the course of the disease by reversing the processes of β cell failure.