Velcade™ (PS-341) is a promising novel agent for multiple myeloma (MM) since one third of patients with advanced disease respond. However, most patients do not respond Velcade™. We have shown that heat shock protein (Hsp)27 plays a crucial role in MM cell resistance to Velcade™. In this study, I will delineate the mechanisms whereby myeloma cells resist Velcade™ in order to design clinical trials to enhance its activity and benefit patients with MM.