The spindle assembly checkpoint is a cellular surveillance mechanism that functions to ensure faithful chromosome segregation during mitosis. Failure of this checkpoint can result in aneuploidy, a state of having abnormal numbers of chromosomes. Most human cancers consist of aneuploid cells, but it is unclear if the aneuploidy is a cause or a consequence of tumorigenesis. Over recent years, mouse models for spindle assembly checkpoint failure have been generated to investigate the biological relevance of the different spindle assembly checkpoint genes and the pathologies associated with chromosome number instability. Most of these models exhibit susceptibility to carcinogenesis. Moreover, one model has led to the identification of the spindle checkpoint protein BubR1 as a regulator of the normal aging process.