Nosocomial infections are a major cause of morbidity in the critically injured. The frequent use of antimicrobials in the critically ill has compounded problem of multidrug resistance organisms. Although nosocomial infections have become an important public health issue in all areas of hospital care, those arising in the Intensive Care Unit (ICU) have become especially problematic with a dramatic increase in resistant organisms. Antimicrobial stewardship is a key component of the multifaceted approach to preventing antimicrobial resistance. Stewardship involves selecting an appropriate drug; optimizing the dose and duration to eradicate infection, while minimizing toxicity and conditions that select for resistant bacterial strains. A surveillance program and empiric antimicrobial policy minimizes ultra-broad spectrum prescriptions. There are challenges to successful stewardship, but its aims are education, prevention of antimicrobial overuse, and minimizing the development of resistance. Pivotal to success are clinicians, microbiologists, knowledge of local resistance patterns, and an antimicrobial policy that optimizes the choice, dose and duration of therapy.