The ubiquitin-proteasome pathway plays an important role in the life of cells by removing damaged or unwanted proteins. Our previous studies helped validate the proteasome as a therapeutic target, and led to the approval of the proteasome inhibitor bortezomib (VELCADE®) for patients with relapsed/refactory multiple myeloma. Despite this advance, the majority of bortezomib-treated patients don't achieve a remission, and many suffer drug-related toxicities such as peripheral neuropathy. While proteasome activity is needed in all cells the proteasome itself comes in different forms. We have identified a novel inhibitor of one subtype, the immunoproteasome, which is found in myeloma cells but not in many other cells, including neural tissues. This agent killed myeloma cells in laboratory studies but spared other cells, while non-specific inhibitors like bortezomib caused death in all of them. These and other findings suggest that the immunoproteasome is a novel, distinct therapeutic target whose inhibition could help patients with myeloma while causing fewer side effects. Additional studies are proposed to examine the utility of this new class of drugs, and in learning their mechanism of action. Taken together, they will help establish a rational framework for taking immunoproteasome-specific inhibitors into clinical trials for patients afflicted with multiple myeloma.