Several possible strategems for overcoming the development of bacterial resistance are discussed. The design of new drugs that resist microbial inactivation is reviewed, with particular emphasis on the aminoglycoside and beta-lactam antibiotics. Examples of alteration of the inactivation site, decreased enzyme affinity, steric hindrance of enzymic inactivation, and semiempirical systematic modification of the parent antibiotic are presented. The role of the 7-alpha-methoxy group in cefoxitin and the cephamycins in conferring stability in the presence of beta-lactamase is best rationalized by its steric bulk. The effects of other 7-alpha-substituents are also discussed.