Abstract: Multiple myeloma (MM) is a malignant clonal disease of the plasma cells in bone marrow. Despite the progress of MM treatment, almost all patients will relapse or become resistant to the prescribed drugs. As such, new treatment targets are urgently needed. As well as genetic defects and bone marrow microenvironment disorders, increasing evidence shows that epigenetic regulation plays an important role in MM. Studies have shown that mutations in epigenetic factors are often related to genomic instability, drug resistance and disease progression. These mutations have been found to increase after treatment, particularly histone methylation and DNA methylation modifying enzymes. Here, we reviewed the progress in histone methylation modification in MM, in particular the role of histone methyltransferases (HMTs) and histone demethylases (HDMs) in the development of MM.