CDC20/CDH1 activates the anaphase-promoting complex (APC) and targets various substrates for degradation, thereby allowing the ordered progression through mitosis and G(1). We have found multiple functional CDH1 homologues in the chick. The transcripts of these novel genes are differentially localized to proliferating, differentiated, and postmitotic tissues. All four proteins bind and form a complex with APC in vitro and in cultural cells and have quantitatively different activities in mediating ubiquitination of various APC substrates. Our results suggest that multiple CDH1s may temporally and spatially regulate APC activity both within and outside of the cell cycle.