Ethnopharmacological relevance The increasing use of traditional herbal medicines around the world requires more scientific evidence for their putative harmlessness. To this end, a plethora of methods exist, more or less satisfying. In this post-genome era, recent reviews are however scarce, not only on the use of new “omics” methods (transcriptomics, proteomics, metabonomics) for genotoxicity, teratogenicity, and nephrotoxicity assessment, but also on conventional ones. Methods The present work aims (i) to review conventional methods used to assess genotoxicity, teratogenicity and nephrotoxicity of medicinal plants and mushrooms; (ii) to report recent progress in the use of “omics” technologies in this field; (iii) to underline advantages and limitations of promising methods; and lastly (iv) to suggest ways whereby the genotoxicity, teratogenicity, and nephrotoxicity assessment of traditional herbal medicines could be more predictive. Results Literature and safety reports show that structural alerts, in silico and classical in vitro and in vivo predictive methods are often used. The current trend to develop “omics” technologies to assess genotoxicity, teratogenicity and nephrotoxicity is promising but most often relies on methods that are still not standardized and validated. Conclusion Hence, it is critical that toxicologists in industry, regulatory agencies and academic institutions develop a consensus, based on rigorous methods, about the reliability and interpretation of endpoints. It will also be important to regulate the integration of conventional methods for toxicity assessments with new “omics” technologies.