Two highly conserved WD40-repeat proteins, Cdc20 and Cdh1/Hct1, have been identified as limiting, substrate-specific regulators for anaphase-promoting complex (APC)-dependent proteolysis. Cdc20 and Cdh1 bind directly to APC and activate its cyclin ubiquitination activity. Cdc20 activates APC at the onset of anaphase, while Cdh1 activates APC from late anaphase through G1. Phosphorylation of Cdh1 by cyclin dependent kinases (Cdks), such as Cdc28, blocked Cdh1-APC interaction and APC activation, while dephosphorylation by the phosphatase Cdc14 restored this activity. Activation of the APC and cyclin degradation is required for exit from mitosis; hence, the phosphorylation of Cdc20 and Cdh1 by Cdks regulate APC activity and may control the precise progression of mitosis.