During acute inflammation, immune homeostasis is lost leading to destructive immunopathology. Homeostasis is normally dependent upon coordinated interactions among the various lymphoid, phagocytic and somatic cells that comprise the immune system. In general, these interactions are tightly regulated to obtain a balance between mechanisms necessary to eliminate harmful pathogens, and overaggressive responses leading to destruction of host tissue. Activation of immunoeffector cells results in pro-inflammatory cytokine up-regulation which in turn also activates the vascular endothelium. Through complex signaling, a positive feedback circuit is established which amplifies and sustains the activity of the inflammatory response resulting in the release of other cytokines and related molecules. If these responses are activated in an uncontrolled fashion with dissemination via the circulation, over the period of time, organs distant from the initial insult can be affected to produce multiple organ failure. Lactoferrin, an iron-binding glycoprotein, is considered an important mediator in host defense against the environmental insults in mammals. By virtue of iron sequestration lactoferrin can control the development of many oxidative stress-driven responses. The purpose of this review is to provide a comprehensive summary of research regarding lactoferrin and its role in homeostasis.