Dietary or caloric restriction (DR or CR), typically a 30%-40% reduction in ad libitum or "normal" nutritional energy levels, has been reported to extend life span and health span in diverse organisms, including mammals. Although the life span benefit of DR in primates and humans is unproven, preliminary evidence suggests that DR confers health span benefits. A serious effort is underway to discover or engineer DR mimetics. The most straightforward path to a DR mimetic requires a detailed understanding of the molecular mechanisms that underlie DR and related life span-enhancing protocols. Increased expression of fibroblast growth factor-21 (FGF21), a putative mammalian starvation master regulator, promotes many of the same beneficial physiological changes seen in DR animals, including decreased glucose levels, increased insulin sensitivity, and improved fatty acid/lipid profiles. Ectopic over-expression of FGF21 in transgenic mice (FGF21-Tg) extends life span to a similar extent as DR in a recent study. FGF21 may achieve these effects by attenuating growth hormone (GH)/insulin-like growth factor-1 (IGF1) signaling. Although FGF21 expression does not increase during DR, and therefore is unlikely to mediate DR, it does increase during short-term starvation in rodents, which is a critical component of alternate day fasting, a DR-like protocol that also increases life span and health span in mammals. Various drugs have been reported to induce FGF21, including peroxisome proliferator-activated receptor-α (PPARα) agonists such as fenofibrate, the histone deacetylase inhibitor sodium butyrate, and adenosine monophosphate (AMP) kinase activators metformin and 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR). Of these, only metformin has been reported to extend life span in mammals, and the extent of benefit is less than that seen with ectopic FGF21 expression. Perhaps the most parsimonious explanation is that high, possibly un-physiological, levels of FGF21 are needed to achieve maximum life span and health span benefits and that sufficiently high levels are not achieved by the identified FGF21 inducers. More in-depth studies of the effects of FGF21 and its inducers on longevity and health span are warranted.