Lipid peroxidation (LPO) occurs as a result of the oxidative deterioration of polyunsaturated fatty acids (PUFA), i.e., those that contain two or more carbon–carbon double bonds. The most apparent feature of the oxidative breakdown of lipids is rancidity, a problem that was recognized centuries ago during the storage of fats and oils. Rancidity persists as a widespread problem in today's society because of the common use of polyunsaturated fats and oils. The outer limiting membrane of cells and membranes of subcellular organelles, e.g., mitochondria, liposomes, peroxisomes, etc., are generally rich in PUFA and their protection from oxidation is essential for the optimal function and survival of the cell. In addition to lipids, cell membranes also contain proteins in varying amounts depending on the unique physiology of the membrane. Thus, the inner mitochondrial membrane, because of its high density of respiratory complex proteins, contains only 20% lipids; this is also the case with chloroplast thylakoid membranes. In contrast, the myelin sheath surrounding axons are up to 80% lipid. Due to the differences in the percentage of lipids in membranes, they are subjected to different degrees of peroxidation. Membranes are fluid structures and optimal membrane fluidity is required for their proper function. When membrane fatty acids are oxidized, cell membranes become viscous (more rigid). Many factors contribute to the oxidation of membrane lipids and, during aging, cell membranes become progressively more rancid and rigid; this contributes to the degenerative signs of aging. The oxidation of lipids is a highly complex process that is initiated when a hydrogen atom is abstracted from a methylene (–CH2–) group by a free radical (Figure ​(Figure1).1). PUFA are particularly susceptible to peroxidative initiation because of their numerous carbon–carbon double bonds. Of the free radicals and other reactive oxygen (ROS) and reactive nitrogen species (RNS) generated within cells, the hydroxyl radical (•OH) is easily capable of initiating LPO. In contrast, the superoxide anion radical (O2•–) is not sufficiently reactive to abstract a hydrogen atom from a lipid molecule. As a consequence of the initiation of lipid breakdown, a lipid peroxyl radical (ROO•) is eventually generated. ROO• are highly reactive and are capable of abstracting a hydrogen atom from a neighboring lipid (causing another initiation event). This is referred to as the propagation phase of LPO. Due to this auto-oxidative chain reaction, a single initiation event could theoretically lead to the oxidation of all lipids in a cellular organelle, or in a cell. Other reactive species which initiate LPO include peroxynitrite anion (ONOO−) and singlet oxygen (1O2). Because of the highly destructive structural and functional nature of LPO, there is great interest in identifying molecules which reduce the initiation and/or progression of the denaturation of PUFA. Figure 1 Schematic representations of lipid peroxidation and melatonin's antioxidant cascade. The metabolites of melatonin, i.e., c3OHM, AFMK, and AMK, are generated when the preceding molecule in the cascade functions in the detoxification of reactive oxygen ... Melatonin and its derivatives as antioxidants What has come to be known as melatonin's antioxidant cascade accounts, presumably in large part, for its ability to reduce oxidative damage, including that to PUFA (Tan et al., 2007). When melatonin functions in the detoxification of radicals, the metabolites that are formed are also radical scavengers. The initial derivative that is produced is cyclic 3-hydroxymelatonin (c3OHM) (Figure ​(Figure1).1). This derivative functions as a radical scavenger to generate N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) which, like its predecessor, neutralizes toxic ROS/RNS. In doing so AFMK is metabolized to N1-acetyl-5-methoxykynuramine (AMK). AMK likewise is capable of defeating radicals and beyond this there may yet be other derivatives that function as antioxidants. Via this cascade of reactions, each molecule of melatonin is predicted to scavenge up to 10 ROS/RNS. This unique property of melatonin makes it highly effective in combatting oxidative stress and LPO. Melatonin is produced in many cells and its synthesis may be upregulated under conditions that elevate oxidative stress in mammals, as happens in plants (Arnao and Hernandez-Ruiz, 2013). Besides its direct actions as a scavenger, melatonin also stimulates the activities of a variety of antioxidative enzymes including manganese and copper-zinc superoxide dismutase, glutathione peroxidase and reductase and glutamylcysteine ligase (Rodriguez et al., 2004). The combined actions as well as its function at the inner mitochondrial membrane where it limits electron leakage (called radical avoidance) makes melatonin exceptionally effective in reducing oxidative stress.