beta-lactamases continue to be the leading cause of resistance to beta-lactam antibiotics, among gram-negative bacteria. In recent years, both the incidence and the prevalence of extended-spectrum beta-lactamases, inhibitor-resistant beta-lactamases, AmpC-type enzymes, and both metallo- carbapenemases and nonmetallo-carbapenemases have increased. These beta-lactamases provide resistance to oximino-cephalosporins, beta-lactam/beta-lactamase inhibitor combinations, cephamycins, and carbapenems, respectively. Strains expressing these beta-lactamases will generate a host of therapeutic challenges as we begin the 21st century.