Genotoxicity data are typically qualitatively interpreted, resulting in a binary classification of chemicals. There's ongoing discourse on the necessity for a shift towards a more quantitative approach. This review explores current opportunities, challenges, and perspectives in achieving a quantitative genotoxicity assessment. The suggested opportunities involve establishing a reference point. Challenges arise due to the limited ability of standard in vivo testing to detect diverse genetic damage and the unclear quantitative relationships between measurable effects and adverse health outcomes. Questions also arise regarding the compatibility of the assumed non-threshold dose–response relationship with DNA-reactive mutagens. While a quantitative genotoxicity assessment approach is case-dependent, there's potential for routine use in prioritization, such as in the Margin of Exposure (MOE) approach. However, further research is crucial to determine if a genotoxicity-derived MOE can reliably indicate a low level of concern. Advancing quantitative genotoxicity assessment requires prioritizing the development of new experimental methods for a more in-depth mechanistic understanding and comprehensive analysis of dose–response relationships.