The clinical applicability of Tumor Necrosis Factor-a pi (TNF) is under renewed investigation because of its successful use in the isolated limb perfusion in patients with irresectable soft tissue extremity sarcomas. The high response rate of > 80% with a similarly successful limb salvage rate in this patient population has led to the submission of TNF for registration for this indication in Europe. Similarly, the agent has been shown to be successful in the isolated limb perfusion setting for tumors other than sarcomas, e.g. melanoma, carcinomas. This has caused renewed interest in TNF alpha and in its application in isolated organ perfusions, such as isolated hepatic perfusion. At the Rotterdam Cancer Center a preclinical-clinical interactive development program has been established dedicated to isolated limb, kidney, liver and lung perfusions and the application of new drugs such as TNF and TNF-mutants in these systems. Moreover a program dedicated to reduce the magnitude of surgical procedures by using occlusion balloon catheters is investigating the techniques and pharmacokinetics of procedures such as balloon catheter mediated hypoxic pelvic perfusions (HPP) and isolated hypoxic hepatic perfusions (IHHP). Here we present an overview of these developments.