It has long been acknowledged that the cephalosporin breakpoints used in most European countries and the USA fail to detect many or most extended spectrum β-lactamases (ESBLs) in Enterobacteriaceae and that all ESBLs are clinically significant. Therefore, microbiological laboratories have undertaken not only regular cephalosporin susceptibility tests based on breakpoints, but also special tests to detect all ESBLs. An increasing accumulation of clinical data implies that the clinical success of third generation cephalosporin therapy is related more to the minimum inhibitory concentration (MIC) than to the presence or absence of an ESBL. However, the breakpoints must be lower than those previously recommended by many breakpoint committees. In Europe, this adjustment has been achieved by EUCAST (European Committee on Antimicrobial Susceptibility Testing) through the ongoing process of harmonising European breakpoints. In the USA, the CLSI recently voted to adopt similar guidelines but are waiting to implement these while revising other β-lactam breakpoints. As Enterobacteriaceae are becoming increasingly resistant, a less ‘diehard’ interpretation of the relationship among MICs, ESBLs and clinical outcome may provide therapeutic alternatives in difficult situations.