Changes in iron homeostatic responses routinely accompany infectious or pro-inflammatory insults. The systemic inflammatory response syndrome (SIRS) and the development of acute lung injury (ALI) feature pronounced systemic and lung specific alterations in iron/heme mobilization and decompartmentalization; such responses may be of pathological significance for both the onset and progression of acute inflammation. The potential for excessive iron-catalyzed oxidative stress, altered pro-inflammatory redox signaling and the provision of iron as a microbial growth factor, represent obvious adverse aspects of altered in vivo iron-handling. The release of hemoglobin during hemolytic disease or surgical procedures such as those utilizing cardiopulmonary bypass procedures further impacts on iron mobilization, turnover and storage with associated implications. Genetic predisposition may ultimately determine the extent to which SIRS and related syndromes develop in response to such changes. The design of specific therapeutic interventions based on endogenous stratagems to limit adverse aspects of altered iron handling may prove of therapeutic benefit for the treatment of SIRS and ALI.