Mature T-cell and NK-cell lymphomas are increasingly being recognized as unique biological entities distinguishable from other forms of lymphomas. Treatment paradigms developed for B-cell lymphomas are considered inadequate for application to these diseases, as indicated by the poor outcome of these patients with the overall 5-year survival remaining below 30% for most histologies. There is a tremendous need for newer treatment options both in the upfront and relapsed setting for T-cell lymphomas. In recent years, there has been a plethora of new targeted agents that have shown promising activity in T-cell lymphomas. The most notable is the novel antifolate pralatrexate that has been approved for the treatment of relapsed and refractory T-cell lymphoma. Other agents include histone deacetylase inhibitors (vorinostat, romidepsin, belinostat), proteosome inhibitors (bortezomib), immunomodulatory agents (lenalidomide), nucleoside analogs (gemcitabine, nalarabine) and targeted antibodies. An improved understanding of the molecular pathogenesis of T-cell lymphomas will help define the role of these agents in the treatment paradigms of T-cell lymphomas both as single agents and as rationally designed combinations and will lead to curative treatments for these difficult diseases.