Cutaneous T-cell lymphoma (CTCL) includes a heterogeneous group of diseases manifested in many cases by a prolonged clinical course. Even patients with advanced clinical disease, including erythroderma, adenopathy, and cutaneous tumors, can respond to a number of conservative therapeutic modalities, including radiation, cutaneous and extracorporeal phototherapy, and interferon. More aggressive systemic therapies are generally reserved for patients with visceral involvement or effaced (LN4) lymph node disease or patients refractory to multiple conservative approaches. Since no survival benefit has been demonstrated for multiagent cytotoxic chemotherapy regimens, this therapy is generally reserved for patients whose disease demonstrates an aggressive clinical course requiring immediate palliation. Durable responses (5+ years) have been reported with purine analogues; however, prolonged immunosuppression and increased frequency of opportunistic infections have been demonstrated. Novel therapeutic agents, including interleukin-2, interleukin-12, the phosphorylase inhibitor peldesine (BCX-34), and bexarotene, have demonstrated activity. The interleukin-2 diphtheria toxin fusion protein, DAB(389)IL-2, has demonstrated a 30% response rate in advanced and refractory CTCL patients. The optimal role of targeted biological therapies in advanced patients will likely be in the minimal disease setting following either chemotherapy or radiation.