Hepatic artery infusion (HAI) chemotherapy has been well developed and is commonly used in the treatment of unresectable hepatic colorectal metastases. However, several important questions are unanswered, such as survival advantage over conventional systemic intravenous chemotherapy, long-term effects on the liver function, and prevention of complications, in particular cholangiosclerosis. Recent investigation into the blood supply of liver tumors challenges the adage that arterial flow is dominant. This review of the merits of regional HAI compared with portal venous infusion (PVI) chemotherapy shows a lack of conclusive data to favor either treatment modality, although a larger experience exists for HAI. Further studies need to be conducted.