The chemical reactivity of membrane lipids is a critical aspect of their function in biological and synthetic membranes. Membrane lipids, particularly phospholipids, spontaneously form bilayer structures, which are essential for biological membranes and have various applications in chemistry and materials science. The unique environment of the lipid bilayer, with a water-poor core and a more polar interfacial region, supports specific chemical reactions and influences the physicochemical properties of the membrane. This review discusses the chemical reactivity of lipids in their membrane form, focusing on conditions where lipids are well hydrated in bilayers. Key topics include lytic reactions of glyceryl esters, oxidation reactions of unsaturated fatty acids and sterols, reactivity of headgroups, and E/Z isomerization of alkenes. The consequences of these reactions for biological activity and biophysical properties are also discussed. The review covers various aspects of lipid reactivity, including hydrolysis, aminolysis, and transesterification. Hydrolysis of glycerophospholipids is discussed, with a focus on the effects of temperature, pH, chain length, membrane composition, and ionic strength. The hydrolysis of plasmalogens is also addressed, highlighting their susceptibility to hydrolysis due to the electron-rich nature of the enol ether. Other hydrolyses, such as those involving lanthanide ions and phosphodiesters, are briefly mentioned. Aminolysis and transesterification reactions are explored, with a focus on the intrinsic lipidation of membrane-embedded molecules. The reactivity of peptides with lipids is discussed, highlighting the role of nucleophilic groups in forming lysolipids and lipidated products. The review also addresses the effects of lipid reactivity on membrane stability, including the impact of hydrolysis products on bilayer permeability and the role of cholesterol in modulating membrane properties. The review emphasizes the importance of understanding lipid reactivity in the context of drug delivery, food science, and cosmetics. It highlights the challenges in studying lipid reactivity, including the complexity of biological systems and the need for advanced analytical techniques. The review concludes with future directions for research, focusing on the relationship between oxidation and hydrolysis, and the prediction of stability in complex formulations.The chemical reactivity of membrane lipids is a critical aspect of their function in biological and synthetic membranes. Membrane lipids, particularly phospholipids, spontaneously form bilayer structures, which are essential for biological membranes and have various applications in chemistry and materials science. The unique environment of the lipid bilayer, with a water-poor core and a more polar interfacial region, supports specific chemical reactions and influences the physicochemical properties of the membrane. This review discusses the chemical reactivity of lipids in their membrane form, focusing on conditions where lipids are well hydrated in bilayers. Key topics include lytic reactions of glyceryl esters, oxidation reactions of unsaturated fatty acids and sterols, reactivity of headgroups, and E/Z isomerization of alkenes. The consequences of these reactions for biological activity and biophysical properties are also discussed. The review covers various aspects of lipid reactivity, including hydrolysis, aminolysis, and transesterification. Hydrolysis of glycerophospholipids is discussed, with a focus on the effects of temperature, pH, chain length, membrane composition, and ionic strength. The hydrolysis of plasmalogens is also addressed, highlighting their susceptibility to hydrolysis due to the electron-rich nature of the enol ether. Other hydrolyses, such as those involving lanthanide ions and phosphodiesters, are briefly mentioned. Aminolysis and transesterification reactions are explored, with a focus on the intrinsic lipidation of membrane-embedded molecules. The reactivity of peptides with lipids is discussed, highlighting the role of nucleophilic groups in forming lysolipids and lipidated products. The review also addresses the effects of lipid reactivity on membrane stability, including the impact of hydrolysis products on bilayer permeability and the role of cholesterol in modulating membrane properties. The review emphasizes the importance of understanding lipid reactivity in the context of drug delivery, food science, and cosmetics. It highlights the challenges in studying lipid reactivity, including the complexity of biological systems and the need for advanced analytical techniques. The review concludes with future directions for research, focusing on the relationship between oxidation and hydrolysis, and the prediction of stability in complex formulations.