The ubiquitin/proteasome-dependent proteolytic pathway plays a role in diverse processes such as cell cycle progression, apoptosis, and antigen presentation by MHC class I, as well as clearance of damaged proteins during stress responses. Its involvement in pathological processes such as inflammation, neurodegenerative diseases, and cancer makes it a promising target for drug discovery. Masucci and colleagues (p. 538) now describe a reporter system for monitoring proteosome activity in living cells. They tagged GFP with sequences that target proteins for degradation by the proteosome. The tagged GFPs are normally degraded rapidly, but they accumulate in cells treated with proteosome inhibitors. These constructs should prove quite useful for designing high-throughput screens for identifying and optimizing novel inhibitors.