The ubiquitin pathway plays a central role in the regulation of cell growth and cell proliferation by controlling the abundance of key cell cycle proteins. Increasing evidence indicates that unscheduled proteolysis of many cell cycle regulators contributes significantly to tumorigenesis and is indeed found in many types of human cancers. Aberrant proteolysis with oncogenic potential is elicited by two major mechanisms: defective degradation of positive cell cycle regulators (i.e., proto-oncoproteins) and enhanced degradation of negative cell cycle regulators (i.e., tumor suppressor proteins). In many cases, increased protein stability is a result of mutations in the substrate that prevent the recognition of the protein by the ubiquitin-mediated degradation machinery. Alternatively, the specific recognition proteins mediating ubiquitination (ubiquitin ligases) are not expressed or harbor mutations rendering them inactive. In contrast, the overexpression of a ubiquitin ligase may result in the enhanced degradation of a negative cell cycle regulator. This chapter aims to review the involvement of the ubiquitin pathway in the scheduled destruction of some important cell cycle regulators and to discuss the implications of their aberrant degradation for the development of cancer.