The rapid decline in the cost of dense genotyping is paving the way for new DNA sequence-based laboratory tests to move quickly into clinical practice, and to ultimately help realize the promise of 'personalized' therapies. These advances are based on the growing appreciation of genetics as an important dimension in science and the practice of investigative pharmacology and toxicology. On the clinical side, both the regulators and the pharmaceutical industry hope that the early identification of individuals prone to adverse drug effects will keep advantageous medicines on the market for the benefit of the vast majority of prospective patients. On the environmental health protection side, there is a clear need for better science to define the range and causes of susceptibility to adverse effects of chemicals in the population, so that the appropriate regulatory limits are established. In both cases, most of the research effort is focused on genome-wide association studies in humans where de novo genotyping of each subject is required. At the same time, the power of population-based preclinical safety testing in rodent models (e.g., mouse) remains to be fully exploited. Here, we highlight the approaches available to utilize the knowledge of DNA sequence and genetic diversity of the mouse as a species in mechanistic toxicology research. We posit that appropriate genetically defined mouse models may be combined with the limited data from human studies to not only discover the genetic determinants of susceptibility, but to also understand the molecular underpinnings of toxicity.