The most common subtypes of primary cutaneous T-cell lymphoma (CTCL) are mycosis fungoides and Sézary syndrome. Clinical manifestations and prognosis in CTCL are highly variable. Improving the management of this incurable disease with limited toxicity is an active area of research. Romidepsin is a novel, well-tolerated histone deacetylase inhibitor with promising activity against advanced stages of CTCL. In November 2009, it was approved by the US Food and Drug Administration for the treatment of CTCL in patients who have received at least one prior systemic therapy. This review focuses on the activity, pharmacology, and safety of romidepsin for the treatment of CTCL.