Of the 340 discrete beta-lactamases that have been identified, the most important groups of enzymes that are continuing to proliferate include the plasmid-encoded cephalosporinases, the metallo-beta-lactamases, and the extended-spectrum beta-lactamases. Resistance to specific beta-lactam-containing antimicrobial agents frequently can be traced to a single beta-lactamase, but this task is becoming more difficult for the clinical microbiology laboratory. Other factors, such as multiple beta-lactamase production, transferable multidrug-resistance genes, alterations in outer-membrane porins, and possible antibiotic efflux, all may contribute to a resistance phenotype. Appreciation of these factors may help the physician make a more informed decision when choosing therapy to try to avoid selection of even more pathogenic strains.