The ubiquitin-proteasome system plays a role in a broad range of cellular functions, including cell growth and proliferation. The dysregulation of the ubiquitination process may lead to tumor development. Bortezomib was the first proteasome inhibitor demonstrating activity either as a single agent or in combination with cytotoxic drugs in a wide spectrum of hematological and solid malignancies. A deeper knowledge of the intrinsic molecular mechanisms that govern the ubiquitin system will uncover more opportunities for therapeutic intervention. In this sense, there are a number of compounds under clinical development that target the E3-ubiquitin ligase family, the deubiquitinating enzymes or the enzymatic machinery of the proteasome. In this article we review the rationale for the use of novel ubiquitin-proteasome system inhibitors in gastrointestinal malignancies.