Cutaneous T-cell lymphomas (CTCLs) are a group of uncommon mature T-cell lymphomas presenting primarily or exclusively in the skin. The most common subtype, mycosis fungoides and its leukemic variant Sézary syndrome, frequently behave as a chronic lymphoma with good prognosis for early-stage disease and shortened survival only for patients in advanced stages. Historically, these patients have experienced excessive toxicity from chemotherapy without durable benefit, leading to current conservative treatment strategies. An increasing number of novel therapies are available or in development. These newer therapies often have unique mechanisms of action and different toxicities with less myelosuppression than traditional cytotoxic chemotherapy. Among these novel systemic therapies are so-called biologic therapies such as retinoids like bexarotene, the fusion toxin denileukin diftitox, lenalidomide, and toll-like receptor agonists. Other important novel or emerging agents include the histone deacetylase inhibitors; a novel antifolate, pralatrexate; the proteasome inhibitor bortezomib; and the purine nucleoside phosphorylase inhibitor forodesine. Even agents considered to be conventional chemotherapy, such as gemcitabine or pegylated liposomal doxorubicin, have demonstrated activity in CTCL at relatively lower doses with less myelosuppression. The mechanisms of action of the novel agents are reviewed as well as available clinical data. As the role of these new agents is better understood, particularly with regard to nonoverlapping toxicities, combination strategies might emerge. Evaluation through carefully designed clinical trials should lead to better, safer, and more effective treatment strategies in the future.