The ubiquitin-proteolytic system (UPS) regulates a variety of cellular and biological processes by controlling the stability of regulatory proteins, in space and time. Not surprisingly, defects in this system have been associated with various syndromes and pathologies, including cancer, illustrating the importance of understanding the regulation and the multiple functions of this system.C. elegansis a powerful model system to identify components of the UPS and to study their function during development in multicellular organisms. InC. elegans,the evolutionarily conserved CRL2LRR-1 E3-ligase is critical for the development of the germline. Inactivation of the CUL-2 scaffold or the LRR-1 substrate-recognition subunit leads to a cell cycle arrest in germline stem cells resulting in sterility. Through a genetic screen, we have identified acul-2temperature-sensitive allele and we have used this allele to show that CUL-2 plays multiple roles in the development of the germline. CUL-2 (1) promotes germ cell proliferation, (2) influences the balance between mitotic proliferation and meiotic differentiation, and (3) inhibits the first step of meiotic prophase. Here, we discuss how CUL-2 regulates and coordinates these different processes. We suggest that ubiquitin-mediated protein degradation constitutes an important additional layer of regulation that contributes to the spatial organization of the germline.