Microbial resistance necessitates the search for new targets and new antibiotics. However, it is likely that resistance problems will eventually threaten these new products and it may, therefore, be instructive to review the successful employment of beta-lactam antibiotic/beta-lactamase inhibitor combinations to combat penicillin resistance. These combination drugs have proven successful for more than two decades, with inhibitor resistance still being relatively rare. The beta-lactamase inhibitors are mechanism-based irreversible inactivators. The ability of the inhibitors to avoid resistance may be due to the structural similarities between the substrate and inhibitor.