Maternal obesity can profoundly affect offspring phenotype and predisposition to obesity and metabolic disease. Carefully controlled studies in precocial and altricial mammalian species provide insights into the involved mechanisms. These include programming of hypothalamic appetite-regulating centers to increase orexigenic relative to anorexigenic drive; increasing maternal, fetal, and offspring adrenal and peripheral tissue glucocorticoid production; and increasing maternal oxidative stress. Outcomes often show offspring sex differences that may play a role in the differential susceptibility of males and females to later-life obesity and other related metabolic diseases.