Oxidation of arachidonic acid leads to the formation of highly reactive gamma-ketoaldehydes now termed isoketals. Isoketals react with proteins at a rate that far exceeds other well studied products of lipid peroxidation such as 4-hydroxynonenal and demonstrate a remarkable proclivity to crosslink these proteins. For these reasons, isoketals have the potential to significantly alter protein function and contribute to disease processes. This article reviews the chemistry of isoketal formation, of their adduction to proteins, and of their proclivity to crosslink proteins, as well as their effects on protein function, and their potential role in diseases associated with oxidative injury.