N-arachidonoylethanolamide and 2-arachidonoylglycerol, are endogenous ligands of cannabinoid receptors, for this reason they are called endocannabinoids. The endocannabinoid system contributes to the regulation of body fat distribution and thereby influences different parameters of the metabolic syndrome. Dietary fatty acids by modulating arachidonic acid availability in phospholipids, may modify the levels of endocannabinoid biosynthetic precursors. Our studies in rats and humans showed that dietary strategies aimed at increasing the incorporation of n-3 PUFAs in tissue phospholipids influenced endocannabinoid levels. However, this was not merely the result of a decreased arachidonic availability, but rather to a modified n-6/n-3 ratio irrespective of the absolute levels of arachidonic acid in phospholipids. In addition, while peripheral tissues were quite responsive, brain was marginally affected by changes in dietary fat. We conclude that the physiological balance of the endocannabinoid system is modified by dietary fatty acids in peripheral tissues in relation to n-6/n-3 PUFAs ratio, influencing the onset of the metabolic syndrome and its cardiovascular consequences. On the other hand, brain seems to be more resistance to these changes, thereby avoiding some of the adverse effects of blocking pharmacologically the CNS cannabinoid receptors.