beta-Lactam antibiotics, viz., penicillin, penicillin derivatives, cephalosporins, cephamycins, carbapenems, monobactams. and monocarbams, are the most widely used of all antimicrobial classes by virtue of their high efficacy and specificity and the availability of several derivatives. The expression of one or several beta-lactamases (beta-lactam antibiotic-inactivating enzymes) represents the most widespread and the most clinically relevant resistance mechanism to these antibiotics. The development of beta-lactam antibiotics has thus been a continuous battle of the design of new compounds to withstand inactivation by the ever-increasing diversity of beta-lactamases. This article traces antibiotic development in response to the evolution of beta-lactamases.