Multiple myeloma affected thousands of new individuals in the United States in 2001 and remains incurable despite conventional and high-dose therapies. Novel treatment approaches are needed which target mechanisms whereby multiple myeloma cells grow and survive in the bone marrow. Encouraging results were obtained recently with a proteasome inhibitor that was shown to decrease tumor cell growth, and phase II clinical trials demonstrated remarkable clinical activity, even complete responses, in patients with refractory relapsed disease. We intend to define the underlying molecular mechanisms of this novel class of drugs in multiple myeloma pathogenesis. These studies will provide the framework for development of more potent and less toxic inhibitors and more effective therapies.