The management of limb-threatening soft tissue sarcomas has not yet been standardized. Although local disease control does not affect overall survival, amputation or highly mutilating surgery may be required, which impairs the patient's quality of life. Various neoadjuvant approaches have been proposed to allow limb-sparing surgery for these locally advanced tumors. With TNFalpha-based hyperthermic isolated limb perfusion, the majority of patients can be spared amputation, with acceptable rates of locoregional and systemic complications. As yet, no other available treatment seems to give comparable results when applied to limb-threatening soft tissue sarcomas. Nevertheless, several issues remain to be addressed, such as the type and dose of drugs, repeatability of the procedure, association with radiotherapy, further indications, and evaluation of response. The authors describe the principles underlying TNFalpha-based hyperthermic isolated limb perfusion, review the worldwide experience so far published, and discuss the above issues. The potential future developments of this locoregional therapeutic approach will also be reported.