There is considerable evidence that the rate of free fatty acid (FFA) oxidation plays a regulatory role in blood glucose homeostasis. Effects of FFA on glycolysis, gluconeogenesis, and blood glucose levels have been well documented in the rat. Attempts to assess their role in man have not yielded clearcut results; nevertheless, a role is suggested by the association of high plasma levels of FFA with glucose intolerance and insulin insensitivity in several endocrine and nutritional disorders. In addition, it has been shown that the hypoglycemia of individuals with Jamaican vomiting sickness is due to hypoglycin, an agent which inhibits FFA oxidation. Further studies are required to define more precisely the interrelationship between FFA and glucose metabolism in man. Pending such studies, theories which implicate excessive FFA metabolism in the pathogenesis of diabetes cannot be adequately evaluated.