An estimated 2-3% of all hospitalized patients become critically ill. These patients are in a state of relative immune exhaustion, which cripples their response to infections. Patients are sicker, have many comorbidities, and undergo complex procedures. This clinical picture, combined with increasing technologies and improved survival, presents unique challenges and demands a high level of services and expertise over a prolonged period of time. Long-term acute care hospitals provide these services, and the migration of chronically critically ill patients to these institutions facilitates defining (and quantifying) the spectrum of disease and how to best manage them. The prevalence of multidrug-resistant organism colonization and infection upon arrival to long-term acute care hospitals is high. Admission screening, and appropriate isolation and infection control practices can prevent transmission of these organisms. The implementation of ventilator-associated pneumonia prevention protocols, blood stream infection prevention protocols, and minimizing Foley urinary catheter use can decrease hospital-acquired infection rates and keep them low. In addition, specific attention is required to environmental services and surface and equipment cleaning. A well organized infection control program and an antimicrobial stewardship program have become indispensable to achieve these goals. All of these key principles and recommendations are also relevant to the chronically ill patient in acute care hospital ICUs and step-down units.