Polyubiquitin-mediated degradation of proteins plays an essential role in various physiological processes including cell cycle progression, transcription and DNA replication and repair. Increasing evidence supports a vital role for the E3 ubiquitin ligase cullin-4, in conjunction with the substrate recognition factor Cdt2 (CRL4Cdt2), for the degradation of multiple cell cycle-regulated proteins to prevent genomic instability. In addition, it is critical for normal cell cycle progression by ensuring the timely destruction of various cell cycle proteins whose deregulated expression impairs cell cycle progression. Here, we summarize our current knowledge about the various roles of the CRL4Cdt2 E3 ubiquitin ligase, and how its activity contributes both to the preservation of genome integrity and to normal cell cycle progression, and how its deregulation may contribute to human cancer.