In May 2003, the U.S. Food and Drug Administration granted the proteasome inhibitor bortezomib (Velcade) fast-track status for the treatment of multiple myeloma. This landmark represented the first approval of a drug targeting the ubiquitin-proteasome system (UPS) for any indication. More recently, at the AACR Special Conference "Ubiquitin and Cancer: From Molecular Targets and Mechanisms to the Clinic" (Orlando, FL, January 18-22, 2006), it became evident that drug discovery in the UPS is experiencing another round of great excitement. The reason--new clinical applications found for bortezomib, along with the promised success of new types of proteasome inhibitors reaching the clinic.