Oxygen is essential for the growth and function of mammalian cells. However, imbalances in oxygen or abnormalitiesin the ability of a cell to respond to oxygen levels can result in oxidative stress. Oxidative stressplays an important role in a number of diseases including atherosclerosis, rheumatoid arthritis, cancer, neurodegenerativediseases and asthma. When membrane lipids are exposed to high levels of oxygen or derivedoxidants, they undergo lipid peroxidation to generate oxidized phospholipids (oxPL). Continual exposure tooxidants and decomposition of oxPL results in the formation of reactive electrophiles, such as 4-hydroxy-2-nonenal (HNE). Reactive lipid electrophiles have been shown to covalently modify DNA and proteins. Furthermore,exposure of cells to lipid electrophiles results in the activation of cytoprotective signaling pathwaysin order to promote cell survival and recovery from oxidant stress. However, if not properly managedby cellular detoxification mechanisms, the continual exposure of cells to electrophiles results in cytotoxicity.The following perspective will discuss the biological importance of lipid electrophile protein adducts includingcurrent strategies employed to identify and isolate protein adducts of lipid electrophiles as well as approachesto define cellular signaling mechanisms altered upon exposure to electrophiles. This article is partof a Special Issue entitled: Oxidized phospholipids—their properties and interactions with proteins.