Bacteria and β-lactam antibiotics may be viewed as protagonists in a never-ending battle. Advantage on either side is always followed by a counterstroke that repositions the participants and sets the stage for the next advance. The chief weapons wielded by bacteria are β-lactamases-enzymes that inactivate β-lactam antibiotics by hydrolysis of the essential β-lactam bond. Fleming, by discovering penicillin, also provided the β-lactam substrate necessary to detect β-lactamases. Abraham and Chain later showed that some bacteria (Escherichia coli) elaborate enzymes capable of "destroying the growth-inhibitory property of penicillin". Following the structural elucidation of penicillin, Abraham demonstrated that inactivation was a consequence of enzyme-catalyzed hydrolysis of the β-lactam bond to give penicilloic acid. Some of these enzymes are extraordinarily efficient: a single P99 β-lactamase molecule can hydrolyze 100 000 molecules of cephaloridine in 1 minute. Development of β-lactam antibiotics stable to β-lactamase has been the most significant achievement since Fleming's initial observations in 1928. From the perspective of a medicinal chemist, the structure-activity relationships involved in the development of this diverse group of agents is fascinating. An understanding of the substructures permitting β-lactamase stability and high intrinsic activity should allow the design of new generations of β-lactams.