Diseases caused by impaired regulation of energy balance, in particular obesity, represent a major global health burden. Although polymorphisms, lifestyle and dietary choices have been associated with differential risk of obesity and related conditions, a substantial proportion of the variation in disease risk remains unexplained. Evidence from epidemiological studies, natural experiments and from studies in animal models has shown that a poor intra-uterine environment is associated causally with increased risk of obesity and metabolic disease in adulthood. Induction of phenotypes that increase disease risk involves the fetus receiving cues from the mother about the environment which, via developmental plasticity, modify the phenotype of the offspring to match her environment. However, inaccurate information may induce an offspring phenotype that is mismatched to the future environment. Such mismatch has been suggested to underlie increased risk of metabolic disease associated with a poor early life environment. Recent studies have shown that induction of modified phenotypes in the offspring involves altered epigenetic regulation of specific genes. Identification of a central role of epigenetics in the aetiology of obesity and metabolic disease may facilitate the development of novel therapeutic interventions and of biomarkers of disease risk.