The ubiquitin-proteasome pathway is the major cellular degradative system for various proteins critical for proliferation, survival and homing of myeloma cells. Bortezomib is the first specific and reversible proteasome inhibitor for clinical application in humans. Phase I studies have defined the maximum tolerated dose and suggested activity against multiple myeloma. From single agent phase II studies, a rate of at least partial responses ranging from 27% for relapsed and refractory to 38% for second-line patients was derived. In comparison with pulsed dexamethasone, bortezomib enabled a higher response rate, a longer time to myeloma progression and a longer survival for patients after one to three prior lines of therapy. Preclinical and clinical phase I studies as well as initial phase II studies combining bortezomib with conventional chemotherapy or thalidomide support the assumption that bortezomib sensitizes myeloma cells to these drugs resulting in additive or synergistic activity.