Velcade (Bortezomib) is a successful new treatment for Multiple Myeloma. It acts by inhibiting the function of the proteasome—a cellular machine for protein degradarion that plays critical roles in the regulation of cell growth. Velcade and two related drugs now in development directly block the proteasome's ability to cleave proteins, though Velcade causes unwanted side effects. Recently we have identified a new molecular target for the development of novel types of drugs that block proteins from ever entering the proteasome,and would thus prevent their degradation. We now hope to find small molecules that inhibit this entry step and that may offer advantages over Velcade in cancer therapy.