Hyperthermic isolated limb perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan was repeatedly reported to achieve extraordinarily high clinical remission rates in advanced and non-resectable soft tissue sarcoma of the limbs, thus avoiding imminent mutilation or amputation for most of those patients. With the limb being isolated throughout the extracorporal perfusion, high doses of recombinant TNF-alpha as well as melphalan can be applied. Basically, TNF-alpha directly affects the vasculature of the tumour and induces a severe inflammation with consecutive deterioration of the tumour capillaries. Furthermore, TNF-alpha increases the tumour-selective uptake of melphalan into the tumour cells thus leading to synergy of antivascular targeted treatment and antineoplastic effects of highest dose chemotherapy supplemented by hyperthermia. Meanwhile, a lot of sarcoma centres in Europe adopted this technique and established referral programmes for patients with non-resectable soft tissue sarcomas of the limbs. Despite these programmes many patients still do not get offered hyperthermic ILP with TNF-alpha and melphalan as a treatment option and modality. This article summarizes multimodality in treatment of soft tissue sarcoma of the limbs and reviews the current status of melphalan-based ILP with TNF-alpha (TM-ILP) and its results, to enable comparison and critical consideration of other treatment options.