Little progress has been made in the systemic treatment of melanoma, that is for disseminated stage IV disease. However, the tumour resistance to therapy, especially chemotherapy can be overcome in melanoma by high doses of anticancer agents administered regionally. The purpose of this paper is to illustrate this concept by two modes of regional treatment namely: (1) isolation perfusion of the limbs with high doses of cytokines and chemotherapy under hyperthermia and (2) local treatment of metastatic melanoma. The third part will be devoted to the role of another regional treatment, radiotherapy, where the association with hyperthermy also looks promising.