Over the last 30 years it has become apparent that specific dietary fatty acids are capable of regulating, either directly or indirectly through various signal pathways, the expression of numerous genes, either positively or negatively. Such nutrient-gene interactions have important effects on cell metabolism, differentiation and growth, and ultimately on disease processes. The present review describes some of the more important fatty acid-gene interactions in relation to health and disease in mammalian species, and focuses on the underlying cell signal mechanisms, including various transcription factors, affected by fatty acids and some of their oxygenated derivatives, e.g. the eicosanoids. The review also attempts to clarify some of the complexities of the effects of fatty acids by suggesting a possible overriding regulation by the redox status of the cell. The latter will at least stimulate controversy in this exciting area of lipid research.