Treatment of mycosis fungoides (MF) is indicated to reduce symptoms, improve clinical appearance, prevent secondary complications, and prevent progression of disease, all of which may have an impact on survival. Treatment of MF includes topical and systemic therapies, which can be administered alone or in combination. Psoralen and ultraviolet A radiation is effective in early-stage MF, inducing complete remissions in most patients. Psoralen and ultraviolet A radiation may also be combined with low doses of interferon (IFN)-alpha to treat stage I/II disease. However, early aggressive therapy with radiation and chemotherapy does not improve the prognosis. Local radiotherapy or total skin electron beam irradiation has been used with success to control advanced skin disease. Extracorporeal photopheresis may also be used successfully, but it is not generally available. Once the disease becomes refractory to topical therapy, IFN-alpha single-agent or combination chemotherapy may be administered, but the duration of response is often less than 1 year and ultimately all patients will relapse and become refractory. Among chemotherapeutic agents, pentostatin, gemcitabine, and liposomal doxorubicin seem to be particularly effective. Response rates after combined modality therapy with total skin electron beam irradiation and chemotherapy/IFN-alpha appear similar to response rates of chemotherapy alone. Therefore, there is a great need for the further development of novel emerging treatment modalities, such as retinoids (ie, bexarotene) and immunotherapeutic agents (ie, cytokines, tumor vaccines, and monoclonal antibodies), all of which appear to have significant therapeutic potential in patients with MF. Biologically based therapies may reduce the need for genotoxic therapies, such as cytostatics and radiotherapy.