This review article by Antonio Ayala, Mario F. Muñoz, and Sandro Argüelles focuses on the biochemical concepts of lipid peroxidation, specifically the production, metabolism, and signaling mechanisms of two primary products of lipid peroxidation: malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE). The authors highlight the significant role of lipid peroxidation in cell biology and human health, noting a substantial increase in research publications over the past four decades. They discuss the physiological and protective functions of MDA and 4-HNE as signaling molecules, which can stimulate gene expression and promote cell survival, as well as their cytotoxic roles in inhibiting gene expression and promoting cell death. The review also covers the in vivo mammalian model systems used to study lipid peroxidation and common pathological processes linked to MDA and 4-HNE. Additionally, the article provides an overview of the enzymatic and nonenzymatic processes involved in the formation and metabolism of these products, emphasizing their importance in understanding oxidative stress and its impact on cellular and tissue function.This review article by Antonio Ayala, Mario F. Muñoz, and Sandro Argüelles focuses on the biochemical concepts of lipid peroxidation, specifically the production, metabolism, and signaling mechanisms of two primary products of lipid peroxidation: malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE). The authors highlight the significant role of lipid peroxidation in cell biology and human health, noting a substantial increase in research publications over the past four decades. They discuss the physiological and protective functions of MDA and 4-HNE as signaling molecules, which can stimulate gene expression and promote cell survival, as well as their cytotoxic roles in inhibiting gene expression and promoting cell death. The review also covers the in vivo mammalian model systems used to study lipid peroxidation and common pathological processes linked to MDA and 4-HNE. Additionally, the article provides an overview of the enzymatic and nonenzymatic processes involved in the formation and metabolism of these products, emphasizing their importance in understanding oxidative stress and its impact on cellular and tissue function.