Since the earliest days of β -lactam therapy, drug hydrolysing enzymes have been found in bacteria. Attempts to overcome this problem have developed in two directions, the production of β -lactams stable to these enzymes and the search for inhibitors of these enzymes. The earliest successful attempts at producing β -lactamase inhibitors was by using fl-lactam antibiotics. Methicillin was successfully used in this role in 1965. However, methicillin and the isoxazolyl penicillins are clinically poor inhibitors, unrealistically high levels of inhibitor being required. Cephalosporins have also been used and cephoxazole plus penicillin is used in veterinary practice. Other cephalosporins such as cefoxitin and moxalactam have β -lactamase inhibitory properties but these are potent antibiotics in their own right. Two naturally-occurring β -lactams, clavulanic acid and sulbactam (CP-45,899), have been extensively investigated. Both are progressive competitive inhibitors and they inhibit the enzymes produced by Staphylococcu.s aureus , Bacteroides fragilis and also the ubiquitous TEM enzyme. They are less effective as inhibitors of the cephalosporinase enzymes. Therefore, the combination of β -lactam plus inhibitor considerably expands the spectrum of the β -lactam alone. To date, the majority of experience, both in vitro and in vivo has been with an inhibitor plus ampicillin or amoxycillin. In the future, no doubt, combinations of inhibitor plus broader spectrum β -lactams, such as ticarcillin or piperacillin, will be considered.