The non-genetic heritability of susceptibility to chronic diseases is often different between males and females. The environment factors can leave epigenetic footprints on the DNA that dictate a coordinated expression of genes. A crucial period is the early development, when the epigenome is being reprogrammed and therefore particularly sensitive to the environment. Sex difference stems from the chromosomal sex (XX/XY) before gonad differentiation and from a later-on complex mix of hormones and X/Y-linked genes regulating autosomal genes. Early exposure interacts with these hormonal and genetic factors, leading to specific reactions, adaptations and outcomes for men and women. With several mouse models of maternal high-fat diet exposure, we demonstrate striking sex specific programming trajectories in different tissues, particularly placenta and liver, in response to the same environmental challenge. Our findings provide proof-of-concept that epigenetic marks and modifiers may be part of the variables that causes sex-specificities. This represents a novel approach to identify sex-specific mechanisms in the origins of health and disease.