AbstractThe chemistry of the reaction of alkylating agents with nucleic acids is briefly reviewed both with respect to the reactive sites and to the destabilization of DNA which results from alkylation. On the basis of these results, mechanisms for mutation by alkylating agents are proposed, and the possible relationships between these and mechanisms for carcinogenesis are discussed. The available evidence suggests that difunctional agents are more effective carcinogens than the corresponding monofunctional agents. This indicates that if carcinogenesis results from mutation then the mutation is most likely to be one resulting from a gross deletion rather than a point change. A study is reported of the binding of a number of H3‐ and C14‐labeled polynuclear aromatic hydrocarbons to the DNA, RNA, and protein of mouse skinin vivoat various times after their application. A firm binding to the cellular constituents was found which persisted in the nucleic acids after extensive purification. Within a limited series of hydrocarbons, a significant positive correlation was observed between the extent of binding of the hydrocarbon to DNA and its carcinogenic power. No such correlation was observed in the binding of hydrocarbon to RNA or protein. Whereas the alkylating agents can react directly with cellular constituents, the hydrocarbons presumably act via reactive metabolites. The nature of these is unknown, but if they were epoxides a fundamentally similar mode of action could be envisaged for both types of carcino