Registration of small molecule pharmaceuticals requires a comprehensive assessment of their genotoxic potential using a standard battery of tests. The genetic toxicity tests of the standard battery are in a period of re-evaluation to assess their utility in human hazard identification and risk assessment. There are concerns with the in vitro mammalian cell assays with respect to the high incidence of positive results and their poor correlation in predicting carcinogenicity. The positive results can necessitate follow-up testing. Approaches for dealing with a positive finding include a weight-of-evidence approach, assessment of mechanism of action, and additional supportive studies.