Several mechanisms render antimicrobials inactive; one of these, β‐lactamase hydrolysis of β‐lactam antimicrobials, is a common and serious problem resulting in loss of antimicrobial activity. Resistance in gram‐negative organisms may be caused by chromosomally or plasmid‐mediated β‐lactamases. Chromosomally mediated resistance may result from exposure to inducer compounds (induction) or by selection of stably derepressed mutants. Plasmids are extrachromosomal elements of DNA that can transfer resistance between bacteria. Common plasmid‐encoded β‐lactamases are the TEM‐ and SHV‐type enzymes, which include the newer extended‐spectrum β‐lactamases. Infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality, and increased cost of treatment. When bacteria develop resistance during antimicrobial therapy therapeutic failure ensues in approximately 50% of patients. Clinical studies demonstrate that resistance mediated by β‐lactamases is a critical issue. Strategies for overcoming it include use of β‐lactam‐β‐lactamase inhibitor combinations, development of new antimicrobial compounds, and use of regimens t