The assessment of the potential of a new drug to cause genotoxicity is a prerequisite for its progression to clinical development. This chapter gives a concise overview of the major aspects relating to genotoxicity, which are relevant in small molecule drug discovery. Testing schemes and assays recommended by regulatory guidelines are outlined. The different ways by which small molecules and their metabolites can elicit genotoxicity by DNA-reactive (direct) or non-DNA-reactive (indirect) mechanisms are discussed. Strategies to mitigate the most prevalent mechanisms of small molecule induced genotoxicity are provided and illustrated by examples.