Aneuploidy is a hallmark of most human cancers, but whether it is a cause or a consequence of cellular transformation remains a subject of debate. The spindle checkpoint functions to prevent aneuploidy and plays a central role in this discussion. The checkpoint gene Mad2 is activated by E2F1 and overexpressed in cells lacking a functional Rb pathway. In this issue of Cancer Cell, Sotillo and coworkers report that Mad2 overexpression leads to chromosomal instability and tumorigenesis, indicating that Mad2 contributes to cancer development after Rb mutation. In a second paper, Weaver et al. report that aneuploidy has both tumor-promoting and -suppressing properties.