Hepatic arterial infusion chemotherapy is a high-dose regional chemotherapy model for the treatment of primary liver cancer and liver metastases. The advantage of regional over systemic delivery of therapeutic agents is critically dependent on their pharmacologic properties. If a drug does not exhibit suitable pharmacokinetics and pharmacodynamics, hepatic arterial delivery will not improve the therapeutic index compared to simple intravenous delivery. Successful liver-directed therapy relies on several principles that must be fulfilled to expect an advantage. Although floxuridine (FUDR) has a unique pharmacokinetic profile that is advantageous for hepatic arterial infusion, optimizing therapy may rely on identification of additional candidate drugs for regional delivery and clinical trials to evaluate the merits of combination therapy, both regional and systemic.