Epigenetic dysregulation is a common hallmark of a number of human cancers, including multiple myeloma (MM), promoting tumor cell proliferation and survival through aberrant protein expression. A number of recent studies using next-generation sequencing platforms have expanded our knowledge of the MM epigenome, supporting the development of therapeutic agents targeting specific abnormal epigenetic processes. For instance, hypermethylation of a number of genes, particularly tumor suppressor genes, and overexpression of histone deacetylases (HDACs) have both been correlated with a poorer prognosis in MM. In particular, overall survival of patients with MM is significantly reduced in patients with higher expression of class I HDACs, and preclinical data have shown that pan-deacetylase inhibitors preferentially targeting class I HDACs induce greater MM-cell killing than those preferentially targeting other HDAC classes. The combination of pan-deacetylase and proteasome inhibition induces synergistic anti-MM effects partially through inhibition of HDAC6 and blockade of aggresome formation, an alternative mechanism for protein degradation in the absence of a functional proteasome. However, recent evidence also suggests the presence of proteasome inhibitor–induced class 1 HDAC transcriptional repression, implying both epigenetic and nonepigenetic mechanisms may cooperate in the synergy between pan-deacetylase and proteasome inhibitors. Additionally, recent work has identified anti-MM synergism between pan-deacetylase inhibitors and inhibitors of pathways integral to the regulation of the actin cytoskeleton, offering a potential new direction in the treatment of MM. Future studies will be aimed at discovering novel deacetylase inhibitor combinations to potently and specifically disrupt pathways integral to the survival of MM.