Based on the results from recent sequencing studies, an extensive catalogue of genetic alterations exists, including oncogenic activation of KRAS, or inactivating mutations in tumor suppressor genes (TSGs) such as TP53, CDKN2A/B, SMAD4 and PTEN, as well as in DNA repair genes (e.g., BRCA) and epigenetic modifiers such as ARID1A. Notably, in about 30–40% of CCA patients, molecularly targetable alterations exist, indicating that precision medicine may be beneficial in a considerable subset of biliary tract cancers. This evidence concerns the gene SMAD4 and cholangiocarcinoma.