Multiple myeloma remains an incurable hematological disease originating from the bone marrow. Many drugs and drug combinations are used to treat multiple myeloma. Although most chemotherapeutics are used to correct the course of the disease and control its progression, drug resistance occurs. For this reason, eliminating the genetic factors that cause the disease may be an option. Apart from a large number of mutations, epigenetic mechanisms may be effective in the formation and maturation of multiple myeloma. The importance of epigenetic regulation in various human diseases is gradually growing in interest, and its contribution to multiple myeloma has recently been investigated. In this chapter, we explain epigenetic changes in multiple myeloma in comparison to prior research. The role of epigenetic mechanisms and chemotherapeutics for the treatment of multiple myeloma were reviewed, and potential epigenetic drug targets and their contribution to therapy were emphasized. The effect and benefaction of the bone marrow microenvironment on epigenetic alterations in multiple myeloma are discussed. There are few studies targeting epigenetic changes in multiple myeloma, but the studies in this chapter provide an important contribution to the literature to inspire future research.