Healthy pancreatic β-cells adapt to systemic insulin resistance to maintain normal blood glucose levels, and a failure of this adaptation leads to type 2 diabetes in humans. While genome-wide association studies have uncovered genetic variants that are associated with type 2 diabetes, it is still insufficient to explain the high prevalence of this disease. Epigenetics is the study of gene expression changes that do not involve DNA sequence alterations such as DNA methylation, histone modification, and non-coding RNAs. Over the last decade, a large number of studies have reported on the role of epigenetics in β-cell biology. In this review, we summarize the epigenetic mechanisms in β-cell adaptation and type 2 diabetes, including alterations in three-dimensional chromatin structure and RNA modifications.