Proteasome inhibition is an entirely novel approach to the treatment of malignant disease. By interfering with the ubiquitin-proteasome degradation system, proteasome inhibitors affect numerous cellular processes that are commonly deregulated in cancer cells including gene transcription, cell-cycle regulation, apoptosis, cell migration and DNA repair. This review outlines the physiology of the ubiquitin-proteasome pathway, discusses preclinical and clinical data regarding the activity of proteasome inhibitors against colon cancer and evaluates the rationale for the use of proteasome inhibitors as monotherapy or in combination with other anticancer therapies (i.e., chemotherapy, radiation therapy and other molecular-targeted therapies) in colon cancer.