Essential fatty acids (EFAs): cis-linoleic acid (LA) and -linolenic acid (ALA) are essential for humans and their deficiency is rare in humans due to their easy availability in diet. EFAs are metabolized to their respective long-chain metabolites: dihomo-gamma-linolenic acid (DGLA), and arachidonic acid (AA) from LA; and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from ALA. Some of these long-chain metabolites form precursors to respective prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), lipoxins (LXs) and resolvins. EFAs and their metabolites may function as endogenous angiotensin converting enzyme and HMG-CoA reductase inhibitors, nitric oxide enhancers, anti-hypertensives, and anti-atherosclerotic molecules. EFAs react with nitric oxide (NO) to yield respective nitroalkene derivatives that have cell-signaling actions via ligation and activation of peroxisome proliferator-activated receptors (PPARs). In several diseases such as obesity, hypertension, diabetes mellitus, coronary heart disease, alcoholism, schizophrenia, Alzheimers disease, atherosclerosis, and cancer the metabolism of EFAs is altered. Thus, EFAs and their derivatives have significant clinical implications.