Eukaryotic organisms maintain karyotypes with constant chromosome number, but polyploid cells that contain more than two sets of chromosomes can frequently be found. On the one hand, polyploidization is likely to provide some beneficial effects, as naturally occurring polyploid cells can be readily found. On the other hand, polyploidization profoundly affects cell physiology, which may be detrimental to cells. Additionally, polyploidy leads often to aneuploidy and diversification of genetic information; therefore, it has always been considered a prominent driving force in evolution. Recently tetraploid-derived aneuploidy was suggested as a possible mechanism for resistance to fungicides. Another prominent example of the effects of tetraploid-derived aneuploidy is cancer, in which up to one-third of tumours likely originate through tetraploid intermediates. Studying the cellular consequences of polyploidization in human cells is challenging. In contrast, polyploid and aneuploid cells can be easily generated and analysed in the budding yeast Saccharomyces cerevisiae as well as in other yeast species. This, together with the naturally occurring yeast polyploids and aneuploids, provides a valuable model to study the effects of abnormal chromosome numbers on cellular physiology. Thus, the yeast model may provide novel insights into the general mechanisms of genomic instability in eukaryotes and improve our understanding of the consequences of ploidy changes and their relevance for disease.