Dietary polyenoic (n-6) and (n-3) fatty acids uniquely regulate fatty acid biosynthesis and fatty acid oxidation. They exercise this effect by modulating the expression of genes coding for key metabolic enzymes and, in doing this, PUFA govern the intracellular as well as the interorgan metabolism of glucose and fatty acids. During the past 20 years, we have gradually elucidated the cellular and molecular mechanism by which dietary PUFA regulate lipid metabolism. Central to this mechanism has been our ability to determine that dietary PUFA regulate the transcription of genes. We have only begun to elucidate the nuclear mechanisms by which PUFA govern gene expression, but one point is clear and that is that it is unlikely that one mechanism will explain the variety of genes governed by PUFA. The difficulty in providing a unifying hypothesis at this time stems from (a) the many metabolic routes taken by PUFA upon entering a cell and (b) the lack of identity of a specific PUFA-regulated trans-acting factor. Nevertheless, our studies have revealed that PUFA are not only utilized as fuel and structural components of cells, but also serve as important mediators of gene expression, and that in this way they influence the metabolic directions of fuels and they modulate the development of nutritionally related pathophysiologies such as diabetes.