Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (NFE2L2/Nrf2) signaling pathway is a pivotal player in the antioxidant response to oxidative and electrophilic stress and can play a role in many human diseases. Activation or inhibition of Nrf2 has been an approach to treating many diseases such as cancer and regulation of this pathway has been thoroughly studied. Recently, epigenetics has emerged as another layer for regulating Keap1-Nrf2. Epigenetics modification is defined as heritable changes to gene expression without changing DNA sequence and various modifications have been found to be involved in regulating Keap1-Nrf2. Therefore, targeting these epigenetic changes on Keap1-Nrf2 provides a potential pathway for modulating Keap1-Nrf2 to treat disease. In this review, several important and recent findings on epigenetic regulation and perspectives on Keap1-Nrf2 are discussed and shared.