Abstract: Multiple myeloma (MM) is a malignant plasmacytoma that remains incurable. Over the past two decades, with the advent of proteasome inhibitors (PIs), such as bortezomib, and immunomodulatory drugs, such as lenalidomide, the prognosis of MM patients has been significantly improved and their survival time has been prolonged. Recent studies have shown that histone deacetylase inhibitors (HDACis) seems to have better anti-myeloma activity and can significantly improve the overall response rate and prolong both progression-free survival and overall survival of MM patients. Moreover, HDACis can also achieve better efficacy in patients previously treated with an immunomodulatory drug or PIs and those displaying resistance to them. This paper aims to summarize the killing mechanism of HDACis in MM cells and its therapeutic effect on MM patients.