The interactions of DNA polymerases with DNA damage during replication and the contributions of these interactions to mutagenesis and genomic stability are outlined. DNA lesions are classified into two distinct categories with respect to transcription, and these are cytotoxic and mutagenic. These two DNA damages can be repaired by transcription-coupled repair (TCR) and transcriptional mutagenesis (TM), respectively. Advances to help understand the mechanisms and implications of TCR and TM in eukaryotic cells are also discussed.