Fibroblast growth factor receptors (FGFRs) are transmembrane tyrosine kinase receptors that belong to the immunoglobulin (Ig) superfamily and bind to fibroblast growth factors (FGFs). The activation of FGFRs is involved in cell survival, proliferation, migration, and differentiation. There are four human FGFR genes (FGFR1-4). Each FGFR comprises of an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. The extracellular ligand binding domain contains three immunoglobulin-like (Ig-like) loops, a short cluster of conserved acidic amino acids, and a heparin binding domain. The Ig-like loop III is the core of the ligand-binding site. Alternative splicing in Ig-like loop III results in IIIb and IIIc isoforms of FGFR1-3, which change the specificity of the receptor. Unlike FGFR1-3, FGFR4 is expressed as a single isoform. The overexpression of FGFR4 has been reported in many tumors including prostate, breast, pancreatic, pituitary, hepatocellular, and gynecological tumors. Overexpression and? polymorphism (Gly388Arg) of FGFR4 have been associated with a more aggressive tumor behavior and anti-cancer drug resistance. Also, the overexpression of FGFR4 Arg388 can up-regulate genes including uPAR and Ehm2, which are known to promote invasion and metastasis. FGFR4 Arg388 also promotes cancer cell migration and invasion by interacting and stabilizing membrane-type 1 matrix metalloproteinase. In vitro studies have shown that FGFR4 can respond to FGF-1, -8, -17, -18, -19, -21, and -23. The FGF19/FGFR4 axis plays an important role in liver bile acid metabolism. Abnormal FGF19/FGFR4 signaling has been shown to cause hepatocellular carcinomas in mice.