Accurate chromosome segregation during cell division is essential for genome integrity. Errors in chromosome segregation are irreversible and lead to a state of aneuploidy where the number of chromosomes in a cell or organism is not a multiple of the haploid number of chromosomes. Aneuploidy reduces fecundity and is a frequent cause of inherited birth defects. In addition, aneuploidy is very common in solid tumors where it is associated with poor patient prognosis. Recent work has revealed the most common pathways by which chromosomes mis-segregate leading to aneuploidy. Moreover, answers to the key question of how cells respond to aneuploidy are beginning to emerge.