Metastatic or primary unresectable cancers confined to the liver are the sole or life-limiting component of disease for many patients with colorectal cancer, ocular melanoma, neuroendocrine tumors or primary colangio- or hepatocellular carcinomas. A number of regional treatment strategies including infusional chemotherapy and local ablative therapy are under clinical development and attest to the difficulty in adequately treating this condition. Isolated hepatic perfusion (IHP) was first clinically applied over 40 years ago, but because of its technical complexity, the attendant potential morbidity, and the lack of documented efficacy, it has not gained widespread application. In light of the remarkable antitumor activity with isolated limb perfusion with tumor necrosis factor (TNF) and melphalan in patients with unresectable extremity sarcoma or in transit melanoma, this regimen has been administered via IHP at several centers worldwide for unresectable liver cancers. IHP with TNF and melphalan can result in significant regression of advanced refractory cancers confined to the liver and, with additional clinical development, will most likely be a more routinely considered option for patients with this condition.