Peripheral T-cell lymphomas (PTCLs) are a rare, heterogeneous group of T-cell- or natural killer cell-derived non-Hodgkin lymphomas. The majority of patients with PTCL experience an aggressive disease course and poor overall survival. Historically, PTCL has been treated with chemotherapy regimens used to treat B-cell lymphomas; however, a lack of durable responses to frontline therapies and few effective options for salvage treatment have led to the development of newer therapies. Romidepsin is a structurally unique, potent, bicyclic class 1 selective histone deacetylase (HDAC) inhibitor that has demonstrated durable clinical responses in patients with relapsed/refractory PTCL, leading to its approval by the US Food and Drug Administration in 2011 for the treatment of PTCL in patients who have received at least one prior therapy. Here, the authors provide an overview of PTCL, review the role of HDAC inhibitors as anticancer agents, discuss romidepsin use in PTCL, and highlight considerations for advanced practitioners (including the management of side effects).