Ulcerative colitis is a common inflammatory bowel disorder associated with considerable morbidity. Its incidence is increasing worldwide. While familial aggregation of ulcerative colitis is a common phenomenon, genome-wide association studies, identifying a plethora of associated genes, have failed to reveal a unifying causative pathway. The well-documented impact of a number of environmental factors on disease occurrence and natural history suggests a major role for epigenetic events. The epigenome-wide association study discussed in this highlight has revealed novel loci linked to colitis and has provided unique insights into the pathophysiology of this disorder information that could translate into new therapeutic approaches.