Diabetes is caused by combined abnormalities in insulin production and action. The pathophysiology of these defects has been studied extensively and is reasonably well understood. Their causes are elusive and their manifestations pleiotropic, likely reflecting the triple threat of genes, environment, and lifestyle. Treatment, once restricted to monotherapy with secretagogues or insulin, now involves complex combinations of expensive regimens that stem the progression but do not fundamentally alter the underlying causes of the disease. As advances in our understanding of insulin action and β-cell failure reach a critical stage, here I draw on lessons learned from our research on insulin regulation of gene expression and pancreatic β-cell dedifferentiation to address the question of how we can translate this exciting biology into mechanism-based interventions to reverse the course of diabetes.