Reactive chemicals have been used to disinfect drinking waters for over a century. In the 1970s, it was first observed that the reaction of these chemicals with the natural organic matter (NOM) in source waters results in the production of variable, complex mixtures of disinfection by-products (DBP). Because limited toxicological and epidemiological data are available to assess potential human health risks from complex DBP mixture exposures, methods are needed to determine when health effects data on a specific DBP mixture may be used as a surrogate for evaluating another environmental DBP mixture of interest. Before risk assessors attempt such efforts, a set of criteria needs to be in place to determine whether two or more DBP mixtures are similar in composition and toxicological potential. This study broadly characterizes the chemical and toxicological measures that may be used to evaluate similarities among DBP mixtures. Variables are discussed that affect qualitative and quantitative shifts in the types of DBP that are formed, including disinfectants used, their reactions with NOM and with bromide/iodide, pH, temperature, time, and changes in the water distribution system. The known toxicological activities of DBP mixtures and important single DBPs are also presented in light of their potential for producing similar toxicity. While DBP exposures are associated with a number of health effects, this study focuses on (1) mutagenic activity of DBP mixtures, (2) DBP cancer epidemiology, and (3) toxicology studies to evaluate similarity among DBP mixtures. Data suggest that further chemical characterization of DBP mixtures and more systematic study of DBP toxicology will improve the quality and usefulness of similarity criteria.