One of the critical emerging problems in modern pathobiology is how cells govern the decision to live or die, and the cost of making such a decision. Nowhere are these questions more poignant than in deciphering the tissue-specific responses to DNA damage. Mutations in DNA repair enzymes, malfunctions in cell cycle regulation, and genetic instability are associated with most somatic cancers. However, in many hereditary diseases arising from mutations in DNA repair proteins, the same dominant mutations that cause cancer in dividing cells are often associated with cell death in terminally differentiated neurons. Context dependent differences in the response to DNA damage are used to make fundamental choices as to cell fate, and are likely to shed light on the mechanisms underlying human disease.