Over the last 20 years the treatment of cutaneous T-cell lymphoma has been in a state of continual change. New therapies are constantly emerging as the search continues for more effective and tolerable disease-specific agents that satisfy medical needs. Therapies under investigation include topical retinoids, fusion molecules like denileukin diftitox, pegylated interferon, interleukin-2, and interleukin-12. Pegylated liposomal doxorubicin, gemcitabine, and chlorodeoxyadenosine also appear to have clinical potential. Other identified agents include vaccines and monoclonal antibodies. This article reviews some of the most recent clinical innovations.