Strategies to improve the use of antimicrobials and to limit the acquisition and spread of resistance are of paramount importance and may influence directly the epidemiology of nosocomial infections. The increasing incidence of nosocomial infections is strongly related to both suboptimal use of antimicrobials and poor compliance with optimal patient care practices. Cross-transmission of resistant bacteria in hospitals results from poor adherence to infection control measures such as hand hygiene and standard precautions, and leads to an increasing reservoir of resistant organisms, that further facilitate the development of resistance. The strategies proposed in this review target both the appropriate use of antimicrobials in order to decrease resistance acquisition, and improvements in health care practices to reduce cross-transmission.