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Aneuploidy is defined as the state of having a chromosome number that is not an exact multiple of the haploid number. In humans, aneuploidy is the major cause of miscarriages and mental retardation. Although aneuploidy was recognized as a common feature of cancer cells more than a century ago, little is known about its consequences on cellular physiology. Whether aneuploidy is a result or plays a causative role in tumor initiation, progression, or maintenance remains unclear. Our research interests are focused on understanding how aneuploidy affects cellular physiology and metabolism, and how aneuploidy influences cell evolution leading to further gross genomic alterations. Utilizing Saccharomyces cerevisiae as a model organism, we generated a series of aneuploid strains, each carrying an additional copy of 1 of the 16 yeast chromosomes and characterized their effects on cell physiology. These experiments demonstrated that aneuploidy confers a proliferation disadvantage and alters cellular metabolism independent of the identity of the extra chromosome. More recently, we showed that aneuploid yeast cells can quickly evolve and acquire common genomic alterations that lead to improved cellular fitness. Several gene mutations that we found to improve fitness regulate protein turnover and sphingolipid metabolism. These findings profoundly alter our understanding of aneuploidy and might potentially allow for the future development of novel anti-cancer therapies.