There is clear evidence that early and appropriate empiric antimicrobial therapy for suspected nosocomial infections reduces the rate of adverse outcomes. This approach necessitates a liberal antimicrobial policy, whereas observational and experimental data also suggest that excessive antibiotic use promotes the emergence of antimicrobial resistance, creating a dilemma for the intensivists and begging the question as to whether minimization of antimicrobial resistance and maximization of individual patient outcomes are mutually exclusive. Contemporary strategies are outlined for the antimicrobial management of ventilator-associated pneumonia, the most common nosocomial infection in the intensive care unit, and the use of institution-specific guidelines, invasive diagnostic approaches, and other objective criteria to ensure adequate, yet not excessive use of antimicrobials are discussed. The focus is then on relative merits of routine antifungal prophylaxis as an example of an attempt to reduce the incidence and adverse consequences of late diagnoses of fungal sepsis. Finally, the advantages and disadvantages of antimicrobial cycling as a means of reducing antimicrobial resistance in the intensive care unit are outlined.