The article reviews the sources of endogenous DNA damage and their contributions to genomic instability in cancer. It highlights the role of various DNA repair pathways, such as base excision repair (BER), mismatch repair (MMR), and nucleotide excision repair (NER), in maintaining genome integrity. The authors discuss how inactivation of these repair pathways or genomic instability due to cellular processes like transcription and replication can lead to mutations. They also explore the impact of chromatin organization on regional mutation rates, emphasizing that early replicating regions are more prone to mutations due to efficient DNA repair mechanisms. The article further examines the influence of oncogenic stress, gene activation, and transcriptional stress on DNA damage and genomic rearrangements. Finally, it concludes by discussing the potential of precision therapies and CRISPR/Cas9 base editing to address genome instability in cancer.The article reviews the sources of endogenous DNA damage and their contributions to genomic instability in cancer. It highlights the role of various DNA repair pathways, such as base excision repair (BER), mismatch repair (MMR), and nucleotide excision repair (NER), in maintaining genome integrity. The authors discuss how inactivation of these repair pathways or genomic instability due to cellular processes like transcription and replication can lead to mutations. They also explore the impact of chromatin organization on regional mutation rates, emphasizing that early replicating regions are more prone to mutations due to efficient DNA repair mechanisms. The article further examines the influence of oncogenic stress, gene activation, and transcriptional stress on DNA damage and genomic rearrangements. Finally, it concludes by discussing the potential of precision therapies and CRISPR/Cas9 base editing to address genome instability in cancer.