The use of hepatic intra-arterial (HIA) chemotherapy is based on the pharmacologic principle that the regional administration of certain drugs can lead to higher drug concentrations at the site of a tumor. This has been studied most extensively in patients with liver-only colorectal metastases. Four large randomized studies have failed to demonstrate a survival advantage of regional treatment over systemic chemotherapy, although two meta-analyses confirmed an improvement in response rate and suggest a trend toward improvement in survival. Two randomized studies have shown improved survival in patients treated with HIA chemotherapy, as compared with those given supportive care, and quality of life also appears to be superior in HIA chemotherapy recipients. The treatment employed in all of the randomized studies was hindered by substantial hepatobiliary toxicity and many surgical complications. Improved surgical techniques and newer chemotherapy combinations appear to have improved phase II results with HIA therapy, leading to a randomized trial now being conducted by the Cancer and Leukemia Group B (CALGB). The role of HIA chemotherapy in adjuvant settings and in other diseases has not been as well-studied, and such uses remain appropriate only for very selected patients. Ultimately, the regional advantage gained by the HIA route may prove to be most advantageous for the delivery of newer biologic agents.