Endogenous DNA damage contributes significantly to genomic instability in cancer. DNA damage arises from normal cellular processes such as transcription and replication, overwhelming DNA repair mechanisms. This leads to mutations and genomic instability, which can drive cancer development. Recent studies highlight the role of endogenous sources of mutation and epigenomic features in cancer evolution. DNA repair pathways, including base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), homologous recombination (HR), and non-homologous end-joining (NHEJ), are crucial for maintaining genome integrity. Deficiencies in these pathways, often due to mutations in genes like BRCA1, BRCA2, and MLH1, are associated with hereditary cancers. Mutational signatures in cancer genomes reflect specific DNA repair defects, such as those in HR, MMR, and NER. These signatures include C>T transitions, T>G transitions, and A>G transversions, which are linked to aging, oxidative stress, and DNA deamination. APOBEC3B and AID are enzymes that can induce mutations, particularly in cancer genomes. Chromatin organization also influences mutation rates, with early replicating regions being more prone to mutations due to increased transcriptional activity and replication stress. Oncogenic stress and gene activation can lead to DNA damage and chromosomal rearrangements, especially in early replicating regions. Transcriptional stress, caused by high levels of transcription, can result in R-loops and DNA breaks, contributing to genomic instability. Topoisomerase activity, particularly non-canonical roles, can also lead to DNA damage and chromosomal rearrangements. Understanding the mechanisms of DNA damage and repair is essential for developing targeted therapies. Precision therapies, such as those based on synthetic lethality, exploit cancer-specific mutations to reduce collateral damage. Advances in DNA repair research and genomic technologies are providing new insights into the causes and mechanisms of genomic instability in cancer, offering opportunities for improved cancer prevention and treatment.Endogenous DNA damage contributes significantly to genomic instability in cancer. DNA damage arises from normal cellular processes such as transcription and replication, overwhelming DNA repair mechanisms. This leads to mutations and genomic instability, which can drive cancer development. Recent studies highlight the role of endogenous sources of mutation and epigenomic features in cancer evolution. DNA repair pathways, including base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), homologous recombination (HR), and non-homologous end-joining (NHEJ), are crucial for maintaining genome integrity. Deficiencies in these pathways, often due to mutations in genes like BRCA1, BRCA2, and MLH1, are associated with hereditary cancers. Mutational signatures in cancer genomes reflect specific DNA repair defects, such as those in HR, MMR, and NER. These signatures include C>T transitions, T>G transitions, and A>G transversions, which are linked to aging, oxidative stress, and DNA deamination. APOBEC3B and AID are enzymes that can induce mutations, particularly in cancer genomes. Chromatin organization also influences mutation rates, with early replicating regions being more prone to mutations due to increased transcriptional activity and replication stress. Oncogenic stress and gene activation can lead to DNA damage and chromosomal rearrangements, especially in early replicating regions. Transcriptional stress, caused by high levels of transcription, can result in R-loops and DNA breaks, contributing to genomic instability. Topoisomerase activity, particularly non-canonical roles, can also lead to DNA damage and chromosomal rearrangements. Understanding the mechanisms of DNA damage and repair is essential for developing targeted therapies. Precision therapies, such as those based on synthetic lethality, exploit cancer-specific mutations to reduce collateral damage. Advances in DNA repair research and genomic technologies are providing new insights into the causes and mechanisms of genomic instability in cancer, offering opportunities for improved cancer prevention and treatment.