There is a striking link between increasing age and the incidence of cancer in humans. One of the hallmarks of cancer, genomic instability, has been observed in all types of organisms. In the yeast Saccharomyces cerevisiae, it was recently discovered that during the replicative lifespan, aging cells switch to a state of high genomic instability that persists until they die. In considering these and other recent results, we suggest that accumulation of oxidatively damaged protein in aging cells results in the loss of function of gene products critical for maintaining genome integrity. Determining the identity of these proteins and how they become damaged represents a new challenge for understanding the relationship between age and genetic instability.