Fetal growth is determined by the interaction between the environment and the fetal genome. The fetal environment, in turn, is determined by the maternal environment and by maternal and placental physiology. There is evidence that the interaction between the fetal environment and genome can determine the risk of postnatal disease, as well as the individual's capacity to cope with the postnatal environment. Furthermore, the role of various forms of maternal constraint of fetal growth in determining the persistence of these responses is reviewed. A limited number of biologic processes can contribute to the mechanistic basis of these phenomena. In addition to immediate homeostatic responses, the developing organism may make predictive adaptive responses of no immediate advantage but with long-term consequences. An evolutionary perspective is provided, as well as a review of possible biologic processes. The "developmental origins of disease" paradigm is a reflection of the persistence of such mechanisms in humans who now live in very different environments from those within which they evolved. The developmental origins paradigm and its underlying mechanistic and evolutionary basis have major implications for addressing the increasing burden of metabolic and cardiovascular disease.