Introduction: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) mainly comprise polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF, primary or post-PV/ET). Therapy in PV and ET focuses on minimizing thrombosis and bleeding risk, while in MF, prolongation of survival is an important goal. Different cytoreductive agents are employed in high risk PV and ET, while the JAK inhibtior ruxolitinib is the cornerstone of therapy in MF. Histone deacetylase inhibitors (HDACi) are pleiotropic agents with diverse epigenetic and non-epigenetic actions, selectively in transformed cells. A number of HDACi have been or are being investigated in MPN. Areas covered: The mechanisms of action of HDACI in neoplastic cells are summarized, and the preclinical rationale and data supporting their development in MPN specifically examined, particularly their synergism with JAK inhibitors. Major findings of clinical trials of HDACi, both alone and in combination with ruxolitinib, in MPN are then discussed, with particular attention to their toxicities and disease-modifying effects. Expert opinion: HDACi are clearly active in MPN, and there is good preclinical rationale for this. Their combination with ruxolitinib in MF is promising, but the long-term tolerability of these agents is an important concern. Further development in PV or ET appears unlikely.