Isolated limb perfusion with melphalan is the treatment of choice for multiple (small) melanoma-in-transit metastases. The use of tumour necrosis factor alpha (TNFalpha) in isolated limb perfusion is successful for treatment of locally advanced limb soft-tissue sarcomas and other large tumours; this approach can avoid the need for amputation. TNFalpha was approved in Europe after a multicentre trial in patients with locally advanced soft-tissue sarcomas, deemed unresectable by an independent review committee; the response rate to isolated limb perfusion with TNFalpha plus melphalan was 76% and the limb was saved in 71% of patients. Moreover, the trial showed the efficacy of isolated limb perfusion of TNFalpha and melphalan against various other limb-threatening tumours such as skin cancers and drug-resistant bony sarcomas. Laboratory models of isolated limb perfusion have helped to elucidate mechanisms of action and to develop new treatment modalities. They have identified TNFalpha-mediated vasculotoxic effects on the tumour vasculature and have shown that addition of TNFalpha to the perfusate results in an increase of three to six times in uptake of melphalan or doxorubicin by tumours. New vasoactive drugs and new mechanisms of action are being discovered. Moreover, isolated limb perfusion is an effective modality for gene therapy mediated by an adenoviral vector. Various clinical phase I-II studies can be expected in the next few years.