New C3-substituted beta-lactamase inhibitors were prepared and evaluated against representative class A and class C enzymes. It was possible to improve simultaneous inhibitory activity of both classes of serine hydrolase. Other inhibitors showed high selectivity for either the class C cephalosporinases or the class A penicillinases. This represents the first time that cephalosporin-derived inhibitors have demonstrated selectivity for the class A beta-lactamases.