Fibroblast growth factor 21 (FGF21) has been proposed as a novel putative therapeutic agent in type 2 diabetes. A large amount of data, predominantly obtained from murine models but also from non-human primates, suggest that FGF21 ameliorates obesity-associated hyperglycemia and hyperlipidemia primarily via effects on adipose tissue and the pancreas. In addition, FGF21 has been reported to play a pivotal regulatory role in starvation and ketosis. However, while it is clear that FGF21 has potent effects in vivo in several animal models, the exact mechanisms remain elusive. Moreover, very recent results from different human cohort studies have shown a paradoxical regulation of plasma FGF21 in obesity and type 2 diabetes as well as other important qualitative differences in the effects and regulation of FGF21 between rodents and humans. This review focuses on the most recently published data on FGF21 with emphasis on results obtained in humans.