Isolated limb perfusion (ILP) with melphalan is effective in the treatment of in-transit metastasis from melanoma, but did not show activity against unresectable soft tissue sarcoma of the extremity. Tumor necrosis factor-α (TNF), a drug that destroys tumor vessels and enhances tumor-selective drug uptake by threefold to sixfold, has changed this situation. Nowadays, ILP with TNF and melphalan is a very well established therapeutic modality for both indications, to prevent limb amputation. There are also reported data on the success of this regimen against multifocal skin tumors, and drug-refractory bony sarcomas.