During cell division, each daughter cell inherits one copy of every chromosome. Accurate transmission of chromosomes requires that the sister DNA molecules created during DNA replication are disentangled and then pulled to opposite poles of the cell before division. Defects in chromosome segregation produce cells that are aneuploid (containing an abnormal number of chromosomes)—a situation that can have dire consequences. Aneuploidy is a leading cause of spontaneous miscarriages in humans and is also a hallmark of many human cancer cells. Recent work with yeast, Xenopus, and other model systems has provided new information about the proteins that control chromosome segregation during cell division and how the activities of these proteins are coordinated with the cell cycle.