We investigate the molecular basis of insulin signal transduction to understand the pathophysiology of diabetes and related disorders, including obesity, infertility, and cardiovascular and retinal disease. Since diabetes is a complicated, multisystem disease, we use mice to integrate our molecular studies with physiology. Transgenic mice lacking the genes for Irs1 or Irs2 form the basis of many of our experimental models. These mice reveal a surprisingly close relation between the molecular regulation of insulin secretion and that of insulin action. We now understand that the IRS2-branch of the insulin/IGF signaling pathways controls pancreatic beta-cell growth, function and survival. Many of our current experiments focus upon way to exploit the IRS2 signaling cascade to restore beta-cell function and prevent or cure diabetes. Diabetes is serious, but only one of the consequences of insulin resistance, as dysregulated insulin signaling is associated with a cohort of systemic disorders—dyslipidemia, hypertension, cardiovascular disease, stroke, blindness, kidney disease female infertility, and neurodegeneration. Therefore, whether better management of inflammatory responses can attenuate insulin resistance and promote betacell function is an important area of investigation. Training opportunities are available to study insulin signaling cascades, and show how this system plays a role in peripheral and central tissues to regulate nutrient homeostasis.