Birth defects are the leading cause of infant mortality in the United States, which has one of the highest infant mortality rates in the developed world. Many of these birth defects can be attributed to pre-existing, or pregestational, diabetes in pregnancy, which significantly increases a mother's risk of having a child with a major birth defect. Strict preconceptional and early pregnancy glucose control, supplementation with multivitamins and fatty acids, and lower glycemic dietary management have been shown to reduce the incidence of birth defects in experimental and epidemiologic studies. However, because more than half of pregnancies are unplanned, these methods are not generalizable across the population. Thus, better interventions are urgently needed. Based on what we know about the molecular pathophysiology of diabetic embryopathy, our laboratory and others are developing interventions against to key molecular targets in this multifactorial disease process.