Novel in vitro and in vivo assays have been developed to improve the reliability of tools employed for identification of genotoxic hazard. Several of the new assays can provide insight into mode-of-action (MoA). As emerging technologies generally used for evaluating human hazard and/or risk, these novel assays require rigorous evaluation and validation before use in a regulatory setting. Validating novel toxicology assays is a continuing labor-intensive challenge. More specifically, many questions arise around choosing reference compounds, and comparing results against the current standard battery used for genotoxicity testing.