Increasing evidence indicates that most human cancers contain multiple chromosomal alterations. These aberrations are the result of mutations produced not only during the initiation of cancer but also during tumor progression. Since the rates of spontaneous mutations exhibited by normal human cells cannot account for the large numbers of mutations routinely reported in human cancers, we argued that cancer cells are genetically unstable; i.e., they express a mutator phenotype. In this review, we consider potential endogenous sources of these mutations and the recent evidence demonstrating that multiple mutations are present in human cancers. These studies, which connect mismatch repair, genomic instability, and cancer, support the mutator phenotype hypothesis. We conclude that, if multiple mutations are necessary for the progression of cancer, then agents designed to delay their accumulation could significantly reduce cancer deaths.