The receptor tyrosine kinase FGFR2 is one of four fibroblast growth factor receptors designated FGFR1-4 that activate FGF signaling upon trans-autophosphorylation of the receptor dimers. Some genetic alterations of FGFR2 lead to aberrant activation of FGFR2 signaling cascades due to the creation of autocrine signaling loop or the release of FGFR2 from autoinhibition. Activating mutations, including FGFR2 N549K which lies within the protein kinase domain, have been associated with multiple types of malignancies. FGFR2 mutations are more common in tumors of hepatobiliary origin than other solid tumor locations and are found in about 7% of hepatobiliary adenocarcinomas. Treatments with pan-FGFR inhibitors and FGFR2 inhibitors have inhibited proliferation in some tumor types and are under investigation.