Increasing evidence indicates that most human cancers contain multiple mutations. The exact number of mutations, their origin, and types remain to be determined. An over-riding question is whether the multiple mutations that accumulate in cancers is rate-limiting for the carcinogenic process. In this review we consider the argument that the large numbers of mutations routinely reported in human cancers cannot be accounted for by the rate of spontaneous mutation observed in normal human cells. We will analyze different mechanisms that might account for the accumulation of mutations in cancer cells. We conclude that cancer cells are genetically unstable; i.e., they exhibit a mutator phenotype. The recent reports of microsatellite instability in a variety of human cancers have provided the first strong evidence for the presence of a mutator phenotype in human cancers. However, we still lack information about the relationship between microsatellite instability and mutations that allow cancer cells to proliferate, invade, and metastasize.