The 2018 Gordon Research Conference on DNA Damage, Mutation and Cancer is developed around the theme of exploiting fundamental knowledge to advance treatment and prevention. Rich and ever-increasing information is available on the specific mutations that are the molecular basis of cancer. Many mutations can be traced to specific types of damage to the DNA, while others arise from DNA replication errors or unknown causes. Technologies are being refined to determine the origins of these mutations, and monitor the accuracy and reproducibility of cancer genomic data. Biological and structural analyses can assess which mutations are functionally relevant. Specific mutations can confer vulnerabilities, making individual cancers more responsive to treatment with DNA damaging agents.