Biliary tract cancers (intrahepatic, perihilar and extrahepatic cholangiocarcinoma, and gallbladder and cystic duct cancers) are uncommon but highly lethal malignancies. Clinical presentation is often late, precluding curative surgical resection in most cases. For advanced disease, therapeutic options are limited to systemic chemotherapy, with suboptimal outcomes. An understanding of the molecular characteristics of biliary tract cancers may allow the clinical development of therapies targeting actionable alterations with the ultimate goal of improving clinical outcomes. We present a comprehensive review of biliary tract cancer genomics and their clinical implications. Alterations in genes in the EGFR-MAPK-PI3K pathway are seen most often. KRAS alterations are highly prevalent; BRAF alterations are mutually exclusive from RAS alterations and much less frequent. PIK3CA alterations are seen mostly in extrahepatic cholangiocarcinoma and gallbladder cancers whereas HER2 amplification is most common in gallbladder cancers. Various tumor suppressor genes, such as TP53 and p16 are also altered often in biliary tract cancers; however, agents to “activate” silenced genes are currently lacking. FGF and IDH pathway alterations are potential targets for therapeutic agents. FGF alterations are typically fusions with other genes, resulting in altered proteins, and are seen most often in intrahepatic cholangiocarcinoma. IDH pathway alterations affect cellular enzymatic processes and are most common in intrahepatic cholangiocarcinoma. Ongoing clinical trials of agents targeting these pathways hold the promise of improving clinical outcomes. [ABSTRACT FROM AUTHOR]