Resistance to third-generation cephalosporins occurs as a result of either the production of high concentrations of chromosomal cephalosporinase or, increasingly, the presence of broad-spectrum plasmid-mediated beta-lactamases. Both cases represent the response of bacteria in the hospital setting to the selection pressure brought to bear by the use of these antibiotics. Continued evolution of the plasmid-mediated enzymes is occurring as new antibiotics are introduced, probably reflecting the process that began when the first beta-lactamase apparently evolved from the penicillin-binding proteins. beta-Lactamase inhibitors offer one approach to dealing with the evolution of resistance to previously beta-lactamase-stable antibiotics.