The p53 tumor-suppressor gene encodes a cell-cycle checkpoint protein that functions in the G1 phase of the cell cycle. When DNA damage is incurred, p53 transactivates a number of downstream genes whose products, with diverse biologic activities, each make a contribution to the cellular response to DNA damage. One major p53-mediated stress response is the G1 cell-cycle arrest, or delay, which probably allows the cell time to repair DNA damage prior to S-phase entry. In cells lacking p53 function, which include most cancer cells, a condition of genomic instability results from checkpoint loss that culminates in gene amplifications, aneuploidy, and other chromosomal aberrations. These abnormalities contribute to the clonal evolution of cancer cells and tumor progression. The role of p53 in radioresistance and chemoresistance is discussed.