In tumorigenesis, aneuploidy is frequently preceded by tetraploidy. Major issues include how tetraploidy arises and how cells can effectively respond to this state. Two recent papers address these issues. Shi and King demonstrate that nondisjunction of chromosomes in mitosis frequently results in tetraploidy through mitotic cleavage failure. Fujiwara et al. demonstrate that p53 null tetraploid cells are highly competent to induce tumors in nude mice. Together, these papers emphasize the unique hazard of tetraploidy and the fact that p53 status has an intrinsic capacity to eliminate tetraploid cells and suppress tumorigenesis. This p53-dependent elimination may represent a checkpoint control.