The recent and rapid worldwide increase in non communicable diseases challenges the assumption that genetic factors are the primary contributors to such diseases. A new dimension, that of the "developmental origins of health and disease" (DOHaD), is at stake and therefore requires a paradigm shift. Maternal obesity and malnutrition predispose the offspring to develop metabolic syndrome, a vicious cycle leading to transmission to subsequent generation(s), with differences in response and susceptibility according to the sex of the individual. Placenta is a programming agent of adult health and diseases. Adaptation in placental phenotype in response to maternal diet and body composition alter fetal nutrient provision. This implies important epigenetic changes that are however still poorly documented in DOHaD studies, particularly concerning overnutrition. Our objective was to investigate the effects of a high fat diet (HFD) on mouse placental development. We used transcriptomic and epigenetic techniques and showed for the first lime that not only the gene sets but aIso the biological functions affected by the HFD differed markedly between the two sexes. Moreover, the expression of genes coding for epigenetic machinery enzymes, as well as global DNA methylation, were highly dynamic during the fetal period (3 stages), clearly differed between the 2 layers of placenta (labyrinth and functional zone) and showed conspicuous ontogenetic sexual dimorphism for epigenetic modifiers. These findings demonstrate a striking sexual dimorphism of programming trajectories in response to the same environmental challenge. Explaining the sex-specific causal variables and how males versus females respond and adapt to environmental perturbations should help physicians and patients anticipate disease susceptibility. Thus, explorations of changes in sexual dimorphism are potentially useful to identify sex-specific disease mechanisms for use in the development of different, more appropriate prevention and treatment strategies for males and females.