Numerous environmental pollutants are considered DNA-damaging agents with defined mutagenic potential. Therefore, toxicological studies have focused mainly on the impact of such substances on human health, mutagenesis and carcinogenesis. The possible effects of cellular processes, such as DNA repair and recombination, as causes of spontaneous mutations and genome instability, however, have been less extensively studied but are of major importance for the reliable assessment of human health risk by the exposure to environmental or occupational chemicals and radiation. Of all DNA lesions known double-strand breaks (DSB) are among the most fatal because they disrupt the continuity of the DNA template essential for DNA replication and transcription. Omitted or imprecise repair of DSB may therefore result in cell killing, small scale mutations, chromosome rearrangements, and carcinogenesis. In the following report, the potential of cellular DSB-repair mechanisms to generate mutations in humans will be discussed.