The production of β-lactamase is the most important mechanism of bacterial resistance to β-lactam antibiotics. Attempts to find an inhibitor of β-lactamase were made as early as the 1940s and 1950s but without success. In the early 1950s, it was found that certain semisynthetic penicillins could function as β-lactamase inhibitors, but none found a clinical place in this capacity. A program of screening microorganisms for the production of naturally occurring inhibitors was begun in 1967. This process led to the discovery of the olivanic acids and clavulanic acid. Clavulanic acid, formulated with amoxicillin and later with ticarcillin, became available for clinical use in 1981. Since the introduction of clavulanic acid, other β-lactamase inhibitors have been developed, including sulbactam and tazobactam. It remains to be seen whether these will have any advantage over clavulanate for clinical use.