Since their first description more than 20 years ago, Escherichia coli and Klebsiella pneumoniae possessing extended-spectrum class A beta-lactamases (ESBLs) continue to thwart our best clinical efforts. In the 'early years' the most common beta-lactamases were of the TEM and SHV varieties. Now, CTX-M enzymes are being discovered throughout the world and are becoming the most prevalent beta-lactamases found in clinical isolates. The K. pneumoniae carbapenemases (KPC) (ESBL-type enzymes that confer resistance to extended-spectrum cephalosporins and carbapenems) present the most significant challenge to date. Structural studies of ESBLs indicate that active site expansion and remodeling are responsible for this extended hydrolytic activity. Continuing questions still exist regarding the optimal detection method for ESBLs. Most relevant are the increasing concerns regarding the status of carbapenems as 'best therapy' for ESBL-producing bacteria in light of the emergence of carbapenemases.