Epigenetic mechanisms may contribute to the pathogenesis of complex diseases. Early or late environmental influences such as intrauterine malnutrition or sedentary lifestyle have been shown to lead to an increased risk of diabetes. Recently, epigenetic mechanisms were shown to be involved in endocrine cell differentiation and islet function. Genomic profiling of pancreatic islets in non-diabetic and diabetic states is needed in order to dissect the contribution of epigenetic mechanisms to the declining proliferation potential of β cells that we see with aging or the β-cell failure observed in diabetes. In-depth understanding of epigenetic landscapes can help to improve protocols for in vitro differentiation towards the β-cell fate, enhance β-cell proliferation, and lead to the discovery of novel therapeutic targets.