Autoxidation of certain polyunsaturated fatty acids (PUFA) produces 4-hydroxy-2-nonenal (HNE). Of all of the many products produced during PUFA autoxidation, HNE is one of the more interesting. It is remarkably cytotoxic, and appears to play a role in certain types of pathology. This manuscript suggests, for the first time, mechanisms that rationalize the production of HNE from PUFA that undergo autoxidation. The mechanisms require, in agreement with the facts, an n-6 fatty acid and iron catalysis.