The identification of factors distinct from the classical beta-adrenergic regulation of brown adipose tissue thermogenic activity is of interest in order to better understand brown fat physiology and to advance in the development of novel strategies to influence brown fat thermogenesis. Recently, the so-called "hormonal FGFs" (and specially fibroblast growth factor-21, FGF21) have emerged as relevant in the control of brown fat thermogenesis. FGF21 is secreted by the liver and by brown fat itself, being able to act in an endocrine and autocrine manner. FGF21 induces the expression of UCP1 and genes involved in the provision of metabolic foodstuff to sustain thermogenesis (i.e. GLUT1) and in mitochondrial oxidation (cytochrome c) both in vivo and in vitro. In brown adipocytes, FGF21 increases cell respiration and induces significantly the oxidation of glucose and palmitate. Injection of FGF21 to mouse neonates increases local temperature in the dorsal area, correspoding to interscapular brown fat location. The action of FGF21 takes place through the interaction of the hormone with a receptor complex in the brown adipocyte surface including conventional FGF receptors (mainly FGFR1) and the co-receptor beta-Kloho, essential for the FGF21 effects. The expression of beta-Klotho is strongly induced during brown adipocyte differentiation. The interaction of FGF21 with the receptor-co-receptor complex causes the activaction of a set of intracellular kinases, mainly p38 MAP-kinase, that lead ultimately to the pattern of induction of gene expression associated with the promotion of thermogesis. The hormonal FGF system appears as a novel factor regulating brown fat thermogenic activity, which deserves further interest for basical and biomedical application purposes.