Fibroblast growth factor‐21 (FGF‐21) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that βKlotho is an integral part of an activated FGF‐21‐βKlotho‐FGF receptor (FGFR) complex thus a critical subunit of the FGF‐21 receptor. Cells lacking βKlotho did not respond to FGF‐21; the introduction of βKlotho to these cells conferred FGF‐21‐responsiveness and recapitulated the entire scope of FGF‐21 signaling observed in naturally responsive cells. Interestingly, FGF‐21‐mediated effects are heparin independent suggesting that βKlotho plays a role in FGF‐21 activity similar to the one played by heparin in the signaling of conventional FGFs. Moreover, in addition to conferring specificity for FGF‐21, βKlotho appears to support FGF‐19 activity and mediates the receptor selectivity profile of FGF‐19. All together, these results indicate that βKlotho and FGFRs form the cognate FGF‐21 receptor complex, mediating FGF‐21 cellular specificity and physiological effects. J. Cell. Physiol. 215: 1–7, 2008. © 2007 Wiley‐Liss, Inc.