The management of critically ill patients necessitates the use of sedatives and analgesics to provide patient comfort and cooperation. These drugs exert profound effects on all organ systems, not only the central nervous system, and this article describes the immunologic effects of the commonly used critical care sedatives: propofol, the benzodiazepines, opioids, and alpha(2)-adrenoceptor agonists. Benzodiazepines, opioids, and possibly even propofol worsen outcome in animal models of infection, whereas preliminary evidence suggests that the alpha(2)-adrenoceptor agonist, dexmedetomidine, may improve outcomes in the setting of infection. Given the burden of sepsis and secondary infections in critical care, choice of sedation may need to be carefully considered to preserve immune responses in critically ill patients.