Maintaining genome integrity is crucial for correctly regulated gene expression. Conversely, the process of transcription fundamentally impinges on genome stability, necessitating cellular mechanisms that lessen the genome destabilizing effect of reading genes. This review provides an overview of our present knowledge of how eukaryotic RNA polymerase II transcription affects, and is affected by, other DNA-related processes such as chromatin remodeling, DNA repair, recombination and replication.