Dietary polyunsaturated fatty acids (PUFA) have effects on diverse physiological processes impacting normal health and chronic diseases, such as the regulation of plasma lipid levels, cardiovascular and immune function, insulin action and neuronal development and visual function. Ingestion of PUFA will lead to their distribution to virtually every cell in the body with effects on membrane composition and function, eicosanoid synthesis, cellular signaling and regulation of gene expression. Cell specific lipid metabolism, as well as the expression of fatty acid-regulated transcription factors, likely play an important role in determining how cells respond to changes in PUFA composition. This review will focus on recent advances on the essentiality of these molecules and on their interplay in cell physiology, leading to new perspective in different therapeutic fields.