When extensive, fibrosis can impair the function of an affected organ. Despite a greater understanding of the causes and processes leading to organ fibrosis, there are a limited number of treatment options with minimal data supporting their utility. Identifying compounds for clinical use that inhibit fibrosis is an active area of investigation. In recent years, evidence for the utility of targeting the ubiquitin-proteasome system (UPS) in the inhibition of fibrosis has grown. Here we review the evidence for the interaction of the UPS with processes driving organ fibrosis, including the transforming growth factor beta pathway. We will also discuss the potential utility and harm of proteasome inhibition in the treatment of organ fibrosis.