Cutaneous T-cell lymphoma (CTCL) is a rare group of mature T-cell lymphomas primarily affecting the skin, with mycosis fungoides (MF) and Sézary syndrome (SS) being the most common subtypes. CTCL is characterized by variable clinical manifestations and prognosis, and current treatments are limited to systemic therapies with limited efficacy and toxicity. Romidepsin, a novel histone deacetylase inhibitor (HDACi), has shown promising activity in preclinical studies and early-phase clinical trials for the treatment of advanced CTCL. It was approved by the US Food and Drug Administration (FDA) in November 2009 for the treatment of CTCL in patients who have received at least one prior systemic therapy. Romidepsin is a lipophilic compound that is converted to an active, reduced form within tumor cells, where it inhibits both class I and II HDACs. Preclinical studies demonstrated its potent cytotoxicity against human tumor cell lines and in vivo efficacy against human and murine tumors. Phase I clinical trials established the safety profile and dose range for further evaluation. Phase II trials showed significant clinical activity, with an overall response rate of 34% and a median duration of response of 13.7 months. The drug was well tolerated, with hematologic toxicities being the most common adverse events. However, cardiac toxicity, including T-wave flattening and ST segment depression, has been a concern in clinical trials. Other toxicities include nausea, asthenia, anorexia, vomiting, and thrombocytopenia. The mechanism of action of romidepsin in CTCL remains unclear, and further research is needed to understand its efficacy and potential combination therapies. Despite unresolved questions, romidepsin has demonstrated significant clinical activity and durability in patients with refractory neoplasms, and future trials are expected to explore its role in both frontline and relapsed settings.Cutaneous T-cell lymphoma (CTCL) is a rare group of mature T-cell lymphomas primarily affecting the skin, with mycosis fungoides (MF) and Sézary syndrome (SS) being the most common subtypes. CTCL is characterized by variable clinical manifestations and prognosis, and current treatments are limited to systemic therapies with limited efficacy and toxicity. Romidepsin, a novel histone deacetylase inhibitor (HDACi), has shown promising activity in preclinical studies and early-phase clinical trials for the treatment of advanced CTCL. It was approved by the US Food and Drug Administration (FDA) in November 2009 for the treatment of CTCL in patients who have received at least one prior systemic therapy. Romidepsin is a lipophilic compound that is converted to an active, reduced form within tumor cells, where it inhibits both class I and II HDACs. Preclinical studies demonstrated its potent cytotoxicity against human tumor cell lines and in vivo efficacy against human and murine tumors. Phase I clinical trials established the safety profile and dose range for further evaluation. Phase II trials showed significant clinical activity, with an overall response rate of 34% and a median duration of response of 13.7 months. The drug was well tolerated, with hematologic toxicities being the most common adverse events. However, cardiac toxicity, including T-wave flattening and ST segment depression, has been a concern in clinical trials. Other toxicities include nausea, asthenia, anorexia, vomiting, and thrombocytopenia. The mechanism of action of romidepsin in CTCL remains unclear, and further research is needed to understand its efficacy and potential combination therapies. Despite unresolved questions, romidepsin has demonstrated significant clinical activity and durability in patients with refractory neoplasms, and future trials are expected to explore its role in both frontline and relapsed settings.