Type 2 diabetes arises when the endocrine pancreas fails to secrete sufficient insulin to cope with metabolic demands resulting from β cell secretory dysfunction, decreased β cell mass, or both. Epidemiologic studies have shown strong relations between poor fetal and early postnatal nutrition and susceptibility to diabetes later in life. Animal models have been established, and studies have shown that a reduction in the availability of nutrients during fetal development programs the endocrine pancreas and insulin-sensitive tissues. We investigated several modes of early malnutrition in rats. Regardless of the type of diet investigated, whether there was a deficit in calories or protein in food or even in the presence of a high-fat diet, malnourished pups were born with a defect in their β cell population, with fewer β cells that did not secrete enough insulin and that were more vulnerable to oxidative stress; such populations of β cells will never completely recover. Despite the similar endpoint, the cellular and physiologic mechanisms that contribute to alterations in β cell mass differ depending on the nature of the nutritional insult. Hormones that are operative during fetal life, such as insulin, insulin-like growth factors, and glucocorticoids; specific molecules, such as taurine; and islet vascularization have been implicated as possible factors in amplifying this defect. The molecular mechanisms responsible for intrauterine programming of β cells are still elusive, but among them the programming of mitochondria may be a strong central candidate.