The correct number of chromosomes is important for the maintenance of healthy cells and organisms. Maintenance of a correct chromosome number depends on the accurate distribution of chromosomes to the daughter cells during cell division, and errors in chromosome segregation result in abnormal chromosome numbers, or aneuploidy. Aneuploidy is typically associated with deleterious effects on organismal and cellular fitness; however, aneuploidy has also been associated with enhanced cellular growth in certain contexts, such as cancer. Another type of deviation from the normal chromosome number can occur when entire sets of chromosomes are added to the normal (diploid) chromosome number, resulting in polyploidy. Whereas polyploidy is found in certain normal tissues and organisms, tetraploidy (four sets of chromosomes) is associated with a number of precancerous lesions and is believed to promote aneuploidy and tumorigenesis. While it is clear that chromosome mis-segregation causes aneuploidy, the effect of aneuploidy on chromosome segregation is less clear. Similarly, it is unclear whether and how tetraploidy may affect chromosome segregation. The work described here shows that aneuploidy can cause chromosome mis-segregation and induces chromosome-specific phenotypic effects. In contrast, tetraploidy does not per se induce chromosome mis-segregation, but enables the accumulation of aneuploidy thanks to a "genetic buffer" effect that allows tetraploid cells to tolerate aneuploidy better than diploid cells.