Aneuploidy has been recognized as a common characteristic of cancer cells for >100 years. Aneuploidy frequently results from errors of the mitotic checkpoint, the major cell cycle control mechanism that acts to prevent chromosome missegregation. The mitotic checkpoint is often compromised in human tumors, although not as a result of germline mutations in genes encoding checkpoint proteins. Less obviously, aneuploidy of whole chromosomes rapidly results from mutations in genes encoding several tumor suppressors and DNA mismatch repair proteins, suggesting cooperation between mechanisms of tumorigenesis that were previously thought to act independently. Cumulatively, the current evidence suggests that aneuploidy promotes tumorigenesis, at least at low frequency, but a definitive test has not yet been reported.