Exposures to certain environmental chemicals, drugs and natural products can result in toxicity in humans and wildlife. The adverse effects of some of these chemicals are mediated by nuclear receptors, which regulate gene expression. Our focus is on understanding the gene expression changes involved in nuclear receptor-mediated toxicity in the liver and endocrine system. We use in vivo rodent and in vitro cell line models to compare human, mouse, and rat responses. Ultimately, our aim is to decrease uncertainties in cross-species and cross-model extrapolations and better model relevant human exposures.