INTRODUCTION : Cholangiocarcinoma (CCA) is a diverse group of fatal malignancies arising from the biliary tract. Surgical resection with negative margin offers the only potentially curative option. The majority of patients present at locally advanced or metastatic stages, when surgical resection is not feasible, highlighting the significance of systemic therapy. Given limited effectiveness of traditional chemotherapy regimens in CCA, many investigators have focused on developing novel molecular therapies targeting key aberrant signaling pathways.Areas covered: We present the main genomic aberrations known to play a key role in cholangiocarcinogenesis and discuss promising targeted therapies in clinical development.In October of 2020, a review of the English literature was performed utilizing PubMed and Web of Science databases for the keywords of 'cholangiocarcinoma', 'biliary tract cancer', and 'targeted therapy'.Expert opinion: Unfortunately, despite encouraging results in preclinical studies, the outcome of clinical trials with established targeted therapies like anti-EGFR medications have been discouraging. Currently, agents targeting FGFR2 fusion and IDH1/2 mutations hold great promise for improving the management of CCA. Future studies focused on enhancing our understanding of key aberrant signaling pathways of cholangiocarcinogenesis and the design of homogeneous and biomarker-driven cohorts are key elements of establishing precision medicine in CCA.