Aneuploidy is one of the most obvious differences between normal and cancer cells. However, there remains debate over how aneuploid cells arise and whether or not they are a cause or consequence of tumorigenesis. One proposed route to aneuploid cancer cells is through an unstable tetraploid intermediate. Supporting this idea, recent studies demonstrate that tetraploidy promotes chromosomal aberrations and tumorigenesis in vivo. These tetraploid cells can arise by a variety of mechanisms, including mitotic slippage, cytokinesis failure, and viral-induced cell fusion. Furthermore, new studies suggest that there might not be a ploidy-sensing checkpoint that permanently blocks the proliferation of tetraploid cells. Therefore, abnormal division of tetraploid cells might facilitate genetic changes that lead to aneuploid cancers.