Cholangiocarcinoma (CCA) is the second most common biliary tract malignancy with a dismal prognosis. Surgical resection with a negative microscopic margin offers the only hope for long-term survival. However, the majority of patients present with advanced disease not amenable to curative resection, mainly due to late presentation and aggressive nature of the disease. Unfortunately, due to the heterogeneous nature of CCA as well as limitations of available chemotherapy medications, traditional chemotherapy regimens offer limited survival benefit. Recent advances in genomic studies and next-generation sequencing techniques have assisted in better understanding of cholangiocarcinogenesis and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in management of CCA with encouraging results in preclinical studies and early clinical trials. In this review, we present emerging therapies for precision medicine in CCA.Copyright © 2020 Elsevier Ltd. All rights reserved.