The need to assess the ability of a chemical to act as a mutagen or a genotoxic carcinogen (collectively termed genotoxicity) is one of the primary requirements in regulatory toxicology. Several pieces of legislation have led to an increased interest in the use of in silico methods, specifically the formation of chemical categories for the assessment of toxicological endpoints. A key step in the development of chemical categories for genotoxicity is defining the organic chemistry associated with the formation of a covalent bond between DNA and an exogenous chemical. This organic chemistry is typically defined as structural alerts. To this end, this article has reviewed the literature defining the structural alerts associated with covalent DNA binding. Importantly, this review article also details the mechanistic organic chemistry associated with each of the structural alerts. This information is extremely important in terms of meeting regulatory requirements for the acceptance of the chemical category approach. The structural alerts and associated mechanistic chemistry have been incorporated into the Organisation for Economic Co-operation and Development (OECD) (Q)SAR Application Toolbox.