Main pathways discussed in this review. (A) Ubiquitin (Ub) is first activated by an E1 enzyme, transferred to a chain-initiating E2 (E2^I), and transferred to a substrate (S). The creation of poly-Ub chains by the APC/C requires an elongating E2 (E2^E). The substrate is presented to the RING-E3 ligase APC/C by a coactivator. The main components of the pathway discussed in the main text are shown. (B) Cells in prometaphase activate the spindle assembly checkpoint (SAC ON condition) through the production of an APC/C inhibitor named the mitotic checkpoint complex (MCC). The MCC binds to the APC/C and inhibits it. Chromosomes are shown in blue, and the microtubules are shown as black fibers. Kinetochores are shown as red or green dots. Kinetochores that are not attached to microtubules (red dots) are believed to catalyze the production of the MCC. Attached kinetochores (green dots) stop producing the inhibitor. Mad2, BubR1, and Bub3 are MCC components. See Mitotic inhibition of the APC/C for details.