Numerous studies support the idea that the complex process of gene expression is composed of multiple highly coordinated and integrated steps. While such an extensive coupling ensures the efficiency and accuracy of each step during the gene expression pathway, recent studies have suggested an evolutionarily conserved function for cotranscriptional processes in the maintenance of genome stability. Specifically, such processes prevent a detrimental effect of nascent transcripts on the integrity of the genome. Here we describe studies indicating that nascent transcripts can rehybridize with template DNA, and that this can lead to DNA strand breaks and rearrangements. We present an overview of the diverse mechanisms that different species employ to keep nascent RNA away from DNA during transcription. We also discuss possible mechanisms by which nascent transcripts impact genome stability, as well as the possibility that transcription-induced genomic instability may contribute to disease.