Hepatic arterial infusion (HAI) provides liver-directed therapy for patients with both advanced hepatobiliary malignancies and metastatic disease to the liver. The historical mainstay of HAI treatment has been the use of 5-fluoro-2-deoxyuridine (floxuridine, FUDR) given its high first-pass metabolism and favorable pharmacokinetic properties. Despite the fact that HAI pump therapy has been utilized in these clinical settings since the 1970s, floxuridine remains the dominant chemotherapy. In this chapter, we review the pharmacokinetics and fundamentals of HAI therapy and provide an analysis of key clinical trials of agents beyond floxuridine that have been used for HAI therapy over the past 15 years. We have included traditional chemotherapy delivered via HAI in combination with systemic biologic therapies as well as novel agents, biologic agents, and autologous immune cell HAI treatments. Finally, we provide a brief review of the potential for HAI peptide receptor radionucleotide therapy (PRRT), potential changes in HAI pump design, and novel dose delivery strategies.