Sphingolipids represent one of the major classes of bioactive lipids. Studies of sphingolipids have intensified in the past several years, revealing their roles in nearly all cell biological processes. In addition, epigenetic regulation has gained substantial interest due to its role in controlling gene expression and activity without changing the genetic code. In this review, we first introduce a brief background on sphingolipid biology, highlighting its role in pathophysiology. We then illustrate the concept of epigenetic regulation, focusing on how it affects the metabolism of sphingolipids. We further discuss the roles of bioactive sphingolipids as epigenetic regulators themselves. Overall, a better understanding of the relationship between epigenetics and sphingolipid metabolism may help to improve the development of sphingolipid-targeted therapeutics.