The host response to microbial invasion in the lung must be sufficiently vigorous to allow for microbial eradication but appropriately controlled to prevent spillover of the response into the systemic circulation. Although inflammatory responses in pneumonia are generally compartmentalized, microbial and host factors can promote disordered systemic responses to lung infection. Assessment of the magnitude of the systemic inflammatory response in pneumonia is of limited clinical value, and attempts to suppress this response have failed to improve clinical outcomes. The systemic inflammatory response that occurs in sepsis and other critical illnesses can substantially impair lung innate and acquired immunity. Mechanisms of critical illness–induced immunoparalysis have been incompletely characterized and are the focus of ongoing clinical and basic investigations.