Fibroblast growth factor 21 (FGF21) has emerged as a key regulator of the metabolic response to fasting. Endoplasmic reticulum (ER) stress is a well-established inducer of hepatic FGF21 expression. X-box binding protein 1 (XBP1) has been strongly implicated in regulating hepatic lipid and glucose metabolism, making it an intriguing candidate for mediating the effect of ER stress on FGF21 expression. To directly determine whether hepatic Xbp1 is required for induction of hepatic Fgf21 in vivo, Olivares and Henkel subjected mice bearing a hepatocyte-specific deletion of Xbp1 to fasting, a ketogenic diet, or pharmacologic ER stress, all potent stimuli of Fgf21 expression. By this, they provide definitive evidence that hepatic Xbp1 is not required for induction of hepatic Fgf21.