We are in the midst of unparalleled epidemics of obesity and type 2 diabetes-complex phenotypes originating at the intersection of genetic and environmental risk. As detailed in other chapters, evidence indicates that non-genetic, or environmental, risk may initiate during prenatal and early postnatal life . Striking examples in humans include the association of low birth weight (LBW) and/or accelerated early growth with increased risk of insulin resistance, obesity, type 2 diabetes (T2DM), and cardiovascular disease (CVD), and the close relationship between maternal obesity or diabetes with childhood obesity. In this chapter, we will focus on the intriguing emerging data from both human and animal models that indicate that intrauterine and childhood exposures can also influence risk for diabetes and cardiovascular disease in subsequent generations. Understanding the mechanisms responsible for these effects is critical in order to develop effective metabolic and nutritional interventions to interrupt such vicious intergenerational cycles potentiating risk for metabolic disorders.