In May 2003, the US Food and Drug Administration (FDA) granted accelerated approval for the use of the first-in-class proteasome inhibitor bortezomib as a third-line therapy in multiple myeloma, and the European Union followed suit a year later. Bortezomib has subsequently been approved for multiple myeloma as a second-line treatment on its own and as a first-line therapy in combination with an alkylating agent and a corticosteroid. Furthermore, bortezomib has also been approved as a second-line therapy for mantle cell lymphoma. In this chapter, the focus is on the current clinical research on bortezomib, its adverse effects, and the resistance of multiple myeloma patients to bortezomib-based therapy. The various applications of bortezomib in different diseases and recent advances in the development of a new generation of inhibitors that target the proteasome or other parts of the ubiquitin-proteasome system are also reviewed.