Whether we consider the division of the simplest unicellular organisms into two daughter cells or the generation of haploid gametes by the most complex eukaryotes, no two processes secure the continuance of life more than the proper replication and segregation of the genetic material. The cell cycle, marked in part by the periodic rise and fall of cyclin-dependent kinase (CDK) activities, is the means by which these two processes are separated. DNA damage and mistakes in chromosome segregation are costly, so nature has further devised elaborate checkpoint mechanisms that halt cell cycle progression, allowing time for repairs or corrections. In this article, we review the mitotic checkpoint mechanism that responds to defects in the chromosome segregation machinery and arrests cells in mitosis prior to anaphase onset. At opposite ends of this pathway are the kinetochore, where many checkpoint proteins reside, and the anaphase-promoting complex (APC), the metaphase-to-interphase transition regulator. Throughout this review we focus on budding yeast but reference parallel processes found in other organisms.