Transcription is an essential process in all living cells. However, transcription also sensitises genomic DNA to damage from a number of endogenous sources. Although various mechanisms protect the integrity of DNA during transcription, transcription-associated genomic instability occurs in normal and malignant cells and, if unrepaired, can result in genomic alterations. Numerous studies have implicated genomic alterations found in cancer genomes to transcription. Hence, transcription-associated genomic instability can be considered as a major driver of cancer development. In this review, we summarise the body of knowledge on transcription-associated genomic instability and highlight recent discoveries in the field on both healthy and malignant cells. We also discuss how transcription-associated DNA damage might promote transforming lesions at cell type- and lineage-specific genes.Oncogene advance online publication, 6 November 2017; doi:10.1038/onc.2017.402.