Bortezomib (VELCADE) is a proteasome inhibitor that not only targets the myeloma cell, but also acts in the bone marrow micro-environment, inhibiting the binding of myeloma cells to bone marrow stromal cells, as well as demonstrating anabolic effects on bone. Intravenous bortezomib, with or without dexamethasone, is effective and well tolerated in patients with relapsed/refractory multiple myeloma, as demonstrated in the phase II CREST and SUMMIT trials, and the phase III APEX trial, and is a recommended treatment for this patient group. Based on the results of another phase III trial, the combination of bortezomib plus pegylated liposomal doxorubicin is also a recommended treatment for patients with relapsed/refractory multiple myeloma. Other bortezomib-combination regimens have demonstrated promising response data in phase II trials in patients with relapsed/refractory disease, although response and survival data for these combinations need to be confirmed in larger phase III trials. Bortezomib was effective and well tolerated when used as part of a first-line regimen in previously untreated patients with multiple myeloma. In the phase III VISTA trial in elderly patients with previously untreated multiple myeloma not eligible for transplantation, bortezomib in combination with melphalan and prednisone was effective and well tolerated and is a recommended treatment regimen for this group of patients. Preliminary data from phase II/III trials in patients with previously untreated multiple myeloma indicate a promising role for the use of bortezomib combined with various other chemotherapeutic agents as induction therapy prior to transplantation.