In the past few years, it has become clear that mutations in epigenetic regulatory genes are common in human cancers. Therapeutic strategies are now being developed to target cancers with mutations in these genes using specific chemical inhibitors. In addition, a complementary approach based on the concept of synthetic lethality, which allows exploitation of loss-of-function mutations in cancers that are not targetable by conventional methods, has gained traction. Both of these approaches are now being tested in several clinical trials. In this Review, we present recent advances in epigenetic drug discovery and development, and suggest possible future avenues of investigation to drive progress in this area.