A significant number of compounds do not proceed in drug discovery due to toxicity issues. The purpose of this study was to evaluate whether gene expression profiles could be identified and used to classify drugs based on the mechanism of toxicity in an in vitro system. Rat hepatocytes were treated with two classes of drugs, aromatic hydrocarbon receptor (AhR) and peroxisome proliferator activated receptor (PPAR) ligands. The results showed that a small set of genes could be identified that could be used to classify new compounds with distinct mechanisms of toxicity.