The complexity of cholangiocarcinoma (CCA) cellularity and the molecular perturbation mechanisms that underlies the diversity of growth patterns of this malignancy remains a clinical concern. Tumors of the biliary system display significant intrinsic chemoresistance, caused by significant stromal involvement and genome-wide tumor heterogeneity, hampering disease remission and palliation as well as promoting the metastatic behavior. It is crucial to advance our present understanding of the risk and molecular pathogenesis of CCA. This will facilitate the delineation of patient subsets based on molecular perturbations and adjust for precision therapies. This article is protected by copyright. All rights reserved.