Decidualisation is the dramatic morphological and functional differentiation of the uterus that occurs in response to embryo implantation. In mice, the progression of decidualisation attenuates with age, leading to higher levels of reproductive failure. Aging is also associated with an accumulation of DNA methylation changes, and impeding methylation diminishes decidualisation; however, our understanding of the epigenetic regulation of decidualisation over the female reproductive life span is still limited, and the subject of Myriam Hemberger and colleagues’ new paper. They first analyse RNA-seq data from uterine tissue samples, and find that the expression of a number of DNA methylation regulators changes during decidualisation. Comparing the methylation profiles at E3.5 (peri-implantation) and E11.5 (later stage of decidual maturation) using MeDIP-seq, they then identify thousands of differentially methylated regions (DMRs) across the genome, with the vast majority being hypermethylated at the later stage. DMRs are associated with genes known to be involved in decidualisation, genes differentially expressed between E3.5 and E11.5, and genes responsive to progesterone. Finally, the authors identify a cohort of CpG islands that are differentially methylated in young versus old E3.5 uteri: the vast majority are hypermethylated in aged samples, and this hypermethylation is associated with lower expression of crucial decidualisation regulators. The early hypermethylation of decidualisation genes may therefore explain the frequent failure of aged uterine tissue to adequately support pregnancy.