Even after complete surgical resection of pulmonary metastases, many patients develop recurrent disease in the thorax despite the use of systemic chemotherapy, dosage of which is limited because of systemic toxicity. Although subsequent operations are feasible and good long-term results have been reported, sufficient functional lung parenchyma must remain. For this reason, new treatment strategies are explored. Similar to isolated limb and liver perfusion, isolated lung perfusion (ILuP) is a promising surgical technique for the delivery of high-dose chemotherapy with minimal systemic toxicity. The use of biologic response modifiers, such as tumor necrosis factor, is also feasible. ILuP with high-dose chemotherapy has proven to be highly effective in the experimental models of pulmonary metastases with a superior survival advantage compared with systemic treatment. Lung levels are significantly higher after ILuP compared with intravenous therapy without systemic exposure. Phase I human studies have shown that ILuP is technically feasible with low morbidity and without compromising the patient's pulmonary function. Further clinical studies are necessary to determine its definitive effect on local recurrence, long-term toxicity, pulmonary function, and survival.