Histone deacetylase inhibitors (HDAC-Is) are a novel class of small molecules being evaluated in clinical trials for a number of different malignancies. HDAC-Is are able to induce differentiation, apoptosis and/or cell cycle arrest of malignant cells selectively. Vorinostat (Zolinza, Merck & Co., Whitehouse Station, NJ, USA) is the first HDAC-I approved by the U.S. Food and Drug Administration for treatment of the cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Vorinostat was active against solid tumors and hematologic malignancies as intravenous and oral preparations in phase I development. In two phase II trials, Vorinostat was safe and effective at an oral dose of 400 mg/day with an overall response rate of 30-31% in refractory advanced patients with CTCL including large cell transformation and Sezary syndrome. The most frequent side effects of vorinostat include gastrointestinal symptoms, fatigue and thrombocytopenia. Vorinostat, in combination with other agents such as radiation therapy and chemotherapy, can have synergistic or additive effects in a variety of cancers in clinical trials.