Essential fatty acids—linoleic and linolenic—are metabolized to long-chain polyunsaturated fatty acids (LC-PUFAs) such as arachidonic acid (AA) and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively, throughout a series of desaturation and elongation steps. LC-PUFAs are essential for a variety of physiological functions including brain development, cardiac function, inflammatory response, and homeostasis. These roles at the cellular level include modulation of signal transduction via effect of bioactive cell membranes and by regulating the expression of a wide array of genes through different transcription factors such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory-element binding protein (SREBP), carbohydrate response-element binding protein (ChREBP) and nuclear factor κB (NFκB) mainly to control the transcription of target genes including those encoding proteins involved with lipid and carbohydrate metabolism, thermogenesis, and cell differentiation. However, more work is required to delineate these actions and to have a better understanding of the beneficial role of LC-PUFAs in order to comprehend the action of these fatty acids in the pathogenesis of various diseases. Integrative analysis including nutritional, biochemical, genetic and immunological studies may provide information about the identification of specific molecular mechanisms involved in the beneficial effects of n3 LC-PUFAs such as DHA and EPA intake and their metabolic derivates on health promotion or disease burden.