Humans are exposed daily to complex mixtures of chemicals, including drinking water disinfection by-products (DBPs) via oral, dermal, and inhalation routes. Some positive epidemiological and toxicological studies suggest reproductive and developmental effects and cancer are associated with consumption of chlorinated drinking water. Thus, the U.S. Environmental Protection Agency (EPA) conducted research to examine the feasibility of evaluating simultaneous exposures to multiple DBPs via all three exposure routes. A cumulative risk assessment approach was developed for DBP mixtures by combining exposure modeling and physiologically based pharmacokinetic modeling results with a new mixtures risk assessment method, the cumulative relative potency factors (CRPF) approach. Internal doses were estimated for an adult female and an adult male, each of reproductive age, and for a child (age 6 yr) inclusive of oral, dermal, and inhalation exposures. Estimates of the daily internal doses were made for 13 major DBPs, accounting for activity patterns that affect the amount of human contact time with drinking water (e.g., tap water consumed, time spent showering), building characteristics (e.g., household air volumes), and physicochemical properties of the DBPs (e.g., inhalation rates, skin permeability rates, blood: air partition coefficients). A novel cumulative risk assessment method, the CRPF approach, is advanced that integrates the principles of dose addition and response addition to produce multiple-route, chemical mixture risk estimates using total absorbed doses. Research needs to improve this approach are presented.