Cholangiocarcinomas are cancers that arise in the peripheral or central bile ducts. They have substantial heterogeneity in their etiologies and histopathological phenotypes, ranging from cholangiolar carcinomas arising from the smallest bile ducts or from dedifferentiating hepatocytes through cellular plasticity, to ductular cancers in medium and large-sized bile ducts. The surgical delineation of intrahepatic, perihilar and distal cholangiocarcinomas does not match the biological classification, as intrahepatic cholangiocarcinomas include both small duct cholangiolar carcinomas and intermediate duct ductular or mucinous cholangiocarcinomas, which have different genomic and genetic characteristics. Despite their overall poor prognosis, cholangiocarcinomas have proven to include the most actionable target-rich types of cancer, with intrahepatic cholangiocarcinomas including relatively high percentages of fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase 1 or 2 mutations, as well as other currently or potentially targetable aberrations. We discuss the etiologies and risk factors for cholangiocarcinomas, review the pathophysiologic basis for tumor molecular heterogeneity in cholangiocarcinoma, and discuss the known links with mutational signatures in subgroups of cholangiocarcinoma, such as oxidative stress, aging, and exogenous exposures. The potential roles of differences in cell type specific replication timing and immunoselective and metabolic pressures are discussed, as are the implications of synergistic or antagonistic oncogenic effects, leading to unique patterns of cooccurrence versus mutual exclusivity of alterations. In addition, we review; the impacts of common genetic variants and known pathogenic germline or somatic variants which predispose carriers to cholangiocarcinoma. Finally, we discuss the role of epigenetics and variations in DNA methylation in heterogeneity of cholangiocarcinoma within the context of evolving treatment options and remaining key gaps in knowledge.