The increasing prevalence of multidrug-resistant organisms (MDRO) poses a major threat to healthcare systems. Critically ill patients are at heightened risk to acquire MDRO infections resulting in longer hospital stays and higher mortality rates. This article provides an overview of preventive measures, divided into Infection Prevention and Control (IPC) and Antimicrobial Stewardship (AMS) approaches. IPC measures focus on the prevention of MDRO spread by applying basic and extended hygiene strategies. While basic hygiene such as hand and surface disinfection are effective in stopping any pathogen transmission, extended hygiene strategies including screening approaches, patient isolation and contact precautions are essential to identify MDRO patients and separate them from other susceptible patients. On the one hand, AMS aims at reducing the development of resistances under selective pressure by rational use of antimicrobials. On the other hand, interdisciplinary AMS-teams provide recommendations to optimize targeted MDRO therapy, including the rational use of "new" antibiotics. By pursuing different starting points, both IPC- and AMS-strategies are necessary in the prevention of MDRO development and transmission.