Antimicrobial resistance is an important global threat to public health. Hospitals, in particular, are increasingly faced with the emergence and transmission of multidrug-resistant organisms (MDROs). In hospitals, MDROs are transmitted via the hands of healthcare workers, from the contaminated environment, or directly from person to person. Although the transmission of MDROs is frequently recognized in acute care facilities, all healthcare settings are affected by MDROs. Given the evolving epidemiology of MDROs and the complexity of managing them across heterogeneous healthcare settings, multimodal strategies should be adopted to control and prevent the transmission of MDROs. It is fundamental to ensure adherence to evidence-based healthcare-associated infection prevention strategies, including hand hygiene, antimicrobial stewardship, and adequate environmental cleaning, and to ensure the reliable performance of basic infection prevention practices known to mitigate the transmission of MDROs. Healthcare-associated infections and MDROs should be surveilled in a standardized manner in order to detect outbreaks and newly introduced MDROs in healthcare facilities. When epidemiologically important pathogens newly emerge in healthcare facilities or to control outbreaks of specific pathogens, active surveillance cultures combined with preemptive isolation and contact precautions can also be implemented. Healthcare facilities should make sure that appropriate strategies are fully implemented, regularly evaluated for effectiveness, and adjusted as needed. Successful prevention and control of MDROs can be accomplished by administrative leadership, financial and human resource commitments by individual healthcare facilities, and continuous governmental efforts to make resources available for infection prevention and control.