Cholangiocarcinoma (CCA) is the second most common primitive liver cancer. Despite recent advances in the surgical management, the prognosis remains poor, with a 5-year survival rate of less than 5%. Intrahepatic CCA (iCCA) has a median survival between 18 and 30 months, but if deemed unresectable it decreases to 6 months. Most patients have a liver-confined disease that is considered unresectable because of its localization, with infiltration of vascular structures or multifocality. The peculiar dual blood supply allows the delivery of high doses of chemotherapy via a surgically implanted subcutaneous pump, through the predominant arterial tumor vascularization, achieving much higher and more selective tumor drug levels than systemic administration. The results of the latest studies suggest that adequate and early treatment with the combination approach of hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy is associated with improved progression-free and overall survival than SYS or HAI alone for the treatment of unresectable iCCA. Current recommendations are limited by a lack of prospective trials. Individualization of chemotherapy and regimens based on selective targets in mutant iCCA are a focus for future research. In this paper we present a comprehensive review of the studies published to date and ongoing trials.