Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone-like protein and a major metabolic regulator. However, several key aspects of FGF21 biology remain poorly understood. Indeed, the list of controversies in the FGF21 field spans a variety of topics, from basic matters such as the anatomic distribution of FGF21 expression and the molecular composition of the FGF21 receptor, to the ultimate question of therapeutic relevance of FGF21-dependent pathways in humans. In this paper, we focus on current challenges in the field in an attempt to provide a balanced overview of FGF21 biology and guide future research into this exciting metabolic target.