The period since the introduction of β-lactam antibiotics for therapeutic pu~poses has been characterized by a number of phases during which the incidence of resistant bacteria causing clinical infections has been high. Initially, penicillin-resistant staphylococci were the problem; more recently, it has been the resistant gram-negatIve bacteria, including anaerobes, that have given cause for concern. Thus novel β-lactam antibiotics with activity against the resistant organisms have been developed. For the staphylococci methicillin, oxacillin, and cloxacillin were introduced, and for gram-negative species, cefuroxime and cefoxitin. Cefotoxin is particularly useful for treatment of infections due to anaerobes and ampicillin-resistant Isolates of Escherichia coli. In all cases the best way to achieve efficacy against resistant bacteria seems to have been to design antibiotics that are insensitive to hydrolysis by β-lactamases.