Cell division is controlled by a highly regulated program to accurately duplicate and segregate chromosomes. An important feature of the cell cycle regulatory program is that key cell cycle proteins are present and active during specifi c cell cycle stages but are later removed or inhibited to maintain appropriate timing. The ubiquitin–proteasome system has emerged as an important mechanism to target cell cycle proteins for degradation at critical junctures during cell division. Two key E3 ubiquitin ligase complexes that target key cell cycle proteins are the Skp1–Cul1–F-box protein complex and the anaphase-promoting complex/cyclosome. This chapter focuses on the role of these E3 ubiquitin ligases and how ubiquitin- dependent degradation of central cell cycle regulatory proteins advances the cell cycle.