The proteasome is a multiprotein complex that regulates the stability of hundreds of cellular proteins and thus, it is implicated in virtually all cellular functions. Most of the time, to be recognized and processed by the proteasome, a protein has to be linked to a chain of ubiquitin molecules. Cell proliferation, apoptosis, angiogenesis and motility, processes with particular importance for carcinogenesis are regulated by the ubiquitin-proteasome system (UPS). In colorectal epithelium, UPS plays a role in the regulation of the Wnt/β-catenin/APC/TCF4 signaling which regulates proliferation of colorectal epithelial cells in the bottom of the crypts and the inhibition of this proliferation as cells move towards colon villi tips. In most colorectal cancers APC (Adenomatous Polyposis Coli) disabling mutations interfere with the ability of the proteasome to degrade β-catenin leading to uninhibited cell proliferation. Other key molecules in colorectal carcinogenesis such as p53, Smad4 and components of the k-ras pathways are also regulated by the UPS. In this review I discuss the role of UPS in colorectal carcinogenesis and colorectal cancer prognosis and aspects of its inhibition for therapeutic purposes.