Mortality related to serious infections in intensive care units (ICUs) is highest if empirical therapy is not active against the organism causing the infection. However, excessive empirical therapy undoubtedly contributes to bacterial resistance to antibiotics, in turn potentially contributing to poor patient outcome. We have reviewed 3 strategies that are increasingly practiced to reduce the hazards of broad empirical therapy, while aiming to ensure that empirical therapy is adequate. The most widely practiced strategy is discontinuation or streamlining of empirical therapy when culture results are available. The second approach is to withdraw certain antibiotic classes (most notably, third-generation cephalosporins) from the ICU antibiotic armamentarium. The third strategy employed is antibiotic cycling. Although this has also appeared to be a successful strategy, currently published studies have used historical controls and thus may be subject to significant bias. Computer-assisted antibiotic prescribing in ICUs may supplement or replace such strategies in the future.