Unresectable primary and metastatic cancers confined to the liver often determine the prognosis for patients with primary hepatic cancers, colorectal cancer, ocular melanoma, and neuroendocrine tumors. Although many locoregional therapies have emerged as options for patients with unresectable liver malignancies, these treatments frequently have limited clinical benefit. Isolated hepatic perfusion (IHP) has emerged as a regional therapy effective in inducing tumor regression in isolated liver metastases from multiple histologies. Tumor necrosis factor alpha (TNF) is a biologic agent well suited to isolated therapy because of its single-dose efficacy, synergistic effect with hyperthermia, and effects on tumor neovasculature. When combined with chemotherapeutic agents in IHP, TNF may improve response rates in patients with hepatic metastases of some histologies. However, there are additional toxicities associated with the administration of TNF and further studies are needed to determine whether TNF confers a clinical advantage in IHP.