Research question Non-genetic heritability of susceptibility to chronic diseases is often different between male and female. The environmental factors to which an individual is exposed can leave an epigenetic footprint that dictates the coordinate expression of genes. A crucial period is the early development, when the epigenome is reprogrammed and therefore particularly sensitive to the environment. The sexual dimorphism results from the chromosomal sex (XX/XY) before gonad differentiation and a later-on complex mix of hormones and X/Y-linked genes regulating autosomal genes. The early exposure interacts with this subtle superposition, leading to specific reactions, adaptation and outcomes for men and women. Methods With several mouse model of maternal high-fat diet exposure, we demonstrate a striking sexual dimorphism of programming trajectories in different tissues (particularly placenta and liver) in response to the same environmental challenge. Results and Conclusion Our findings provide proof-of-concept that the epigenetic marks and modifiers may be part of the sex-specific causal variables. Their study represents a novel approach to identify sex-specific mechanisms in the origins of health and disease. The discovery of such factors should help physicians and patients anticipate disease susceptibility and may help the development of different preventative and treatment strategies precisely adapted to males and females.