Currently, isolated limb perfusion (ILP) attracts major interest in the treatment of soft tissue sarcoma and melanoma confined to the limb. The procedure combines innovative approaches such as hyperthermia, the use of cytokines, as well as the administration of high-dose chemotherapy. Although used since more than 40 years, the basic knowledge on the mode of action of ILP is still limited. Besides regional toxicity, systemic effects following the application of rhTNF in the perfusion circuit have to be taken into account. Furthermore, WHO criteria of tumor response are rarely met after perfusion of sarcomas. To overcome this, new modalities based on tumor metabolism are currently under investigation. Also the clinical decision on how to proceed after a successful ILP is discussed.