Histone lysine acetylation is regulated by both histone deacetylases (HDACs) and histone acetyl transferases. Inhibition of deacetylases induces hyperacetylate of target proteins and has a crucial role in the epigenetic regulation of gene expression mediating cell survival and proliferation. Therefore, HDAC inhibitors have emerged as novel therapeutic agents for cancers, including multiple myeloma (MM). Recent studies revealed that HDAC inhibitors trigger hyperacetylation of not only histones, but also non-histone proteins regulating cell growth and survival, revealing the complexity of mechanism of action of HDAC inhibitors. Many HDAC inhibitors have already shown significant anti-MM activities in preclinical studies and are under evaluation in clinical trials.