The nongenetic heritability of susceptibility to chronic diseases is often different between males and females. Environmental factors can leave epigenetic footprints on DNA that regulate gene expression. Early development is a crucial period during which the epigenome is being reprogrammed and is therefore particularly sensitive to the environment. Sex differences stem from the chromosomal sex (XX/XY) before gonad differentiation and later on by a complex mix of hormones and regulation of autosomal gene expression by X-/Y-linked genes. Early environmental exposure interacts with these hormonal and genetic factors, leading to sexually dimorphic 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 cause sexual dimorphism. This represents a novel approach to identify sex-specific factors in the origins of health and disease.