Advances in our understanding of the molecular mechanisms underlying the pathophysiology of sepsis have generated considerable efforts in manipulating the host response during this frequently lethal condition. While existing trials of immune modulation have been largely unsuccessful, an appreciation for the roles of individual organ systems in sepsis is important to enable clinicians to discern how each functions as both a target for injury and a contributor to the derangement in homeostasis seen in sepsis. Such awareness will encourage treatment decisions aimed at optimizing conventional therapy while minimizing the adverse effects of supportive care, and it may also guide the incorporation of newer immunomodulatory therapeutics into our existing modalities. This article discusses the lung's response to sepsis, from the standpoint of organ dysfunction related to sepsis as well as its participation in the generation and maintenance of the systemic inflammatory state.