Cell cycle progression is mainly controlled by the hetero-dimeric protein kinase complex named SPF (S-phase promoting factor) and MPF (M-phase promoting factor), consisting of CDKs and the regulator cyclins, which are involved in G1/S and G2/M transitions, respectively. Moreover, SPF is modulated by not only various oncoproteins positively, but also tumor suppresive gene products negatively. These regulator proteins are extremely unstable in cells, oscillating during cell cycle, and cell cycle stage-dependent destruction of specific factors is required for cell cycle progression, but molecular mechanism of their destabilization remains to be clarified. The ubiquitin-proteasome system is responsible for selective- and ATP-dependent degradation of various types of short-lived proteins in the cytoplasm and the nucleus. In this article, we review briefly the proteolytic pathway mediated by ubiquitin and the proteasome, and the degradation mechanism of major cell cycle protein factors, such as Mos, p53, cyclin B, Fos/Jun and NFkappaB/IkappaB.