The rationale for hepatic intra-arterial chemotherapy (HACT) is based on the predominantly arterial vascularization of liver metastases (HM). The intra-arterial route of administration thus increases the exposure of tumor cells to cytotoxic agents while limiting systemic toxicity. Chemotherapy is administered through a catheter placed in the gastroduodenal artery by either a surgical or percutaneous approach. Several anticancer agents can be administered to hepatic metastases from colorectal cancer (HMCRC) by HACT. Fluorodeoxyuridine (FUDR), used mainly in the United States, has a high intrahepatic extraction rate but also has intrinsic hepatobiliary toxicity. The HACT route is less suitable for irinotecan, since its active metabolite requires first-pass metabolism. In France, oxaliplatin is the most commonly used agent administered by HACT in combination with intravenous chemotherapy according to a 5-FU-Leucovorin protocol. The three main indications for HACT are: (1) potentially resectable HMCRC, (2) adjuvant treatment after resection of HMCRC in patients at high risk of intrahepatic recurrence, (3) palliative treatment of patients with primarily intra-hepatic disease that is definitely unresectable. In the setting of potentially resectable HMCRC, HACT can increase the chemotherapeutic response rate and improve the rate of secondary resectability. In the adjuvant setting, HACT seems to improve disease-free survival after complete resection of HMCRC in patients at high risk of intrahepatic recurrence. Finally, in the palliative setting, HACT prolongs progression-free survival, even in patients whose disease has progressed with intravenously administered oxaliplatin.