Cutaneous T-cell lymphomas (CTCLs) are rare lymphomas that arise primarily in the skin and are treated with skin-directed therapies in early-stage disease. Systemic therapy is indicated once skin-directed therapy is ineffective or for advanced-stage disease. CTCLs tend to be poorly responsive to chemotherapy and are incurable except for allogeneic stem cell transplantation. Recently, a new class of agents called histone deacetyalse inhibitors (HDACis) have shown remarkable activity in T-cell lymphomas in general and CTCLs in particular. Oral vorinostat and intravenous romidepsin are two HDACis that are now approved by the US FDA for use in patients with relapsed CTCLs. Several other HDACis are currently in clinical trials for CTCLs and other diseases and, although these agents vary by chemical structure and potency, the results of the ongoing clinical trials will eventually reveal if there are differences in clinical activity as well. The exact mechanism of action of these agents is unknown, but they are thought to affect the acetylation status of histones and other proteins in the cell and epigentically modulate transcription and other cellular activities. This leads to a myriad of downstream effects on cell cycle, apoptosis and differentiation. The following review summarizes the known biological mechanisms and clinical activity of various HDACis in the treatment of CTCLs and tries to define their role in the treatment paradigm of these unusual disorders.