Despite over 100 years of study, the role of aneuploidy in cancer remains poorly understood. This review highlights the advances in understanding the causes and consequences of aneuploidy. Recent work has illuminated ways in which aneuploidy could have either tumor-promoting or tumor-suppressing effects, similar to what is known for other forms of genetic instability such as telomere attrition [Maser RS, DePinho RA: Connecting chromosomes, crisis, and cancer. Science 2002, 297:565-569]. We explore the possibility that aneuploidy could be just another type of 'mutation', with potential beneficial and deleterious effects, depending on the chromosomes involved and the specific selective pressures the cells experience. We also discuss the potential therapeutic implications of changes in physiology associated with aneuploidy.