Most primary cutaneous lymphomas remain localized in the skin for a long time, and they are treated preferentially with skin-directed therapies. However, a number of systemic treatments is used, either in combination with skin-directed therapies or, when the disease disseminates to other organs, as the sole treatment. Conventional chemotherapy is not very effective in the skin. The treatment of disseminated T-cell lymphomas is rarely curative, and single drugs are generally used. Some systemic treatments are cytostatics, e.g., methotrexate, gemcitabine, and doxorubicine; some are immune modularoty, e.g., retinoids, interferons, and extracorporal photophoresis; and some are new targeted drugs, e.g., histone deacetylase inhibitors, brentuximab vedotin, mogamulizumab, and alemtuzumab. Non-myeloablative allogeneic transplant may be used in patients whose disease cannot be adequately controlled with other measures. Indolent primary cutaneous B-cell lymphomas are treated with rituximab if disseminated. For the aggressive primary cutaneous B-cell lymphomas the primary treatment is rituximab combined with conventional combination chemotherapy. Newer targeted drugs are being investigated.