The increasing prevalence of metabolic diseases is alarming and highlights the need for more effective and safer therapies to treat these diseases. Recent evidence from several animal studies indicates that FGF21 induces numerous beneficial metabolic changes without apparent adverse effects. These results suggest that FGF21 could be a novel and attractive drug candidate for the treatment of cardiovascular disease, obesity and type 2 diabetes. The pharmacology of FGF21, molecular mechanisms contributing to the actions of this compound, and knowledge gaps to be addressed to allow further exploration of the therapeutic potential of this molecule are discussed in this review.