Donkin et al. propose that dynamic changes in the epigenome of human spermatozoa in response to the environment may underlie the heritability of obesity. Micrococcal nuclease sequencing (MNase-seq), small non-coding RNA (sncRNA) sequencing and reduced-representation bisulfite sequencing (RRBS) were used to characterize nucleosome positioning, sncRNA expression, and DNA methylation, respectively, in spermatozoa from 13 lean, glucose-tolerant and 10 obese, glucose-intolerant men. These approaches yielded a comprehensive epigenomic profile specific to obesity; sncRNA expression and DNA methylation patterns differed substantially between lean and obese men. In a separate cohort of men with morbid obesity, weight loss (resulting from bariatric surgery) led to marked remodelling of the obesity-associated DNA methylation pattern of spermatozoa. DNA methylation was affected mainly in genetic loci that have previously been implicated in the central control of appetite.