Objective: To assemble the available clinical data on the prevention of antimicrobial resistance in the intensive care unit (ICU) setting. Data Source: A MEDLINE database search and references from identified articles were employed to obtain the literature relating to the prevention of antimicrobial resistance in the ICU. Conclusions: The ICU presents a unique environment for the conduct of clinical research. The closed physical space with centralized patient management and efficient data recovery allows important clinical questions to be evaluated in a timely manner. Antimicrobial resistance has emerged as an important determinant of mortality for patients in the ICU. Additionally, there is currently a limited pipeline of new agents for the treatment of emerging bacteria with new resistance genes that pose an increasing threat to the ICU patient. Effective strategies for the prevention of antimicrobial resistance within ICUs are available and should be implemented aggressively. These strategies can be divided into non-pharmacologic infection-control strategies (e.g., routine hand hygiene, infection-specific prevention protocols) and antibiotic management strategies (e.g., shorter courses of appropriate antibiotics, narrowing of the antimicrobial spectrum on the basis of culture results). Additional studies conducted in ICUs are needed urgently to identify the optimal approaches for the management of antibiotics in order to balance the need for efficacy with the ability to minimize resistance.