The Anaphase Promoting Complex (APC) has been characterized to play pivotal roles in regulating the timely cell cycle progression by forming two functionally distinct E3 ubiquitin ligase sub-complexes, APC(Cdc20) and APC(Cdh1). Interestingly, recent studies have shown that Cdh1 is functioning as a tumor suppressor whereas Cdc20 may function as an oncoprotein to promote the development and progression of human cancers. In this review, we will discuss the physiological role of Cdc20 and its downstream substrates in vitro and in the transgenic mouse model reminiscent of the pathogenesis of human cancers. Furthermore, we summarize recent findings to indicate that Cdc20 may represent a promising therapeutic target, thus development of Cdc20 inhibitors could be useful for achieving better treatment outcome of cancer patients.