The operation of the mitotic checkpoint. The cell cycle is driven by cyclin-dependent kinases (CDKs), which are activated by binding to cyclins that are specific for the different phases of the cell cycle and determine the targets of the kinases. Exit from each phase of the cell cycle occurs on degradation of the bound cyclin. The CDK-cyclin complex that is required for entry into mitosis is CDK1-cyclin B, and cells are driven from G2 into mitosis by its sudden activation. Exit from mitosis at anaphase occurs on activation of the anaphase-promoting complex (APC), a large ubiquitin ligase that targets cyclin B for degradation. The securin that holds the mitotic chromosomes together at metaphase is also tagged for degradation by the APC. The mitotic checkpoint is an external monitoring system that by itself is not required for mitotic progression but detects the presence of chromosomes that are not attached to the mitotic spindle via their kinetochores and, in their presence, initiates a cascade that prohibits activation of the APC and thus chromosome separation and exit from mitosis. When the last kinetochore attaches to microtubules the checkpoint becomes satisfied, allowing APC activation and progress towards mitotic exit. However, even when satisfied, the checkpoint pathway continues to survey for unattached kinetochores, which, should they arise, readily re-impose the block.