The prognosis of patients with irresectable liver metastases derived from colorectal cancer is invariably poor; unfortunately, these tumours show only minor responses to conventional anticancer agents. The best responses have been obtained by fluoropyrimidines delivered as continuous infusion into the hepatic artery (HAI): their rapid uptake and detoxification by liver cells results in relatively low systemic drugs levels. This approach increases mean survival duration from 17 to 26 months and, in few patients, causes "down-staging" that may result in resectability. To improve opportunities for chemotherapy, the technique of 1-hour recirculating perfusion of the vascularly isolated liver (isolated hepatic perfusion, IHP) was developed. If leakage to the systemic circulation is negligible-and the compounds used do not readily cause hepatotoxicity-IHP allows usage of drug doses that would be fatal if delivered systemically. Because alkylating agents generally have steep dose-response curves, mitomycin C (MMC) and melphalan (L-PAM) entered phase I/II studies on IHP. Using these drugs, IHP was performed in principle as a single procedure in 60 otherwise untreated patients at our institution. However, despite preliminary data that indicate impressive clinical responses are obtained, improvement over HAI will probably be minor. Because IHP is a complicated way of drug delivery, one could argue that its use is justified only when it has the potential to kill all tumour cells in the liver. We critically discuss the possibilities of IHP and/or the use of gene therapy in an IHP setting.