Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of lymphomas that are characterized by primary skin involvement. Mycosis fungoides (MF) and Sézary syndrome (SS), the two most common subtypes of CTCL, can be difficult to manage clinically as there are few effective treatment options available. Recently, histone deacetylase inhibitors (HDACi) have emerged as promising therapies with favorable adverse effect profiles, compared with traditional chemotherapies. In this article, we review the published literature to evaluate the role of HDACi in the treatment of CTCL. Specifically, we (1) briefly discuss the molecular rationale for the use of HDACi in CTCL; (2) compare the efficacy, tolerability, and adverse effects of HDACi; (3) review the cardiac safety data; and (4) discuss optimization of therapy with HDACi in the treatment of CTCL.