Inflammation is the body s way of defending itself against noxious stimuli and pathogens. Under normal circumstances, the body is able to eliminate the insult and subsequently promote the resolution of inflammation and the repair of damaged tissues. The concept of homeostasis is one that not only requires a fine balance between both pro-inflammatory mediators and pro-resolving/anti-inflammatory mediators, but also that this balance occurs in a time and space-specific manner. This review examines annexin A1, an anti-inflammatory protein that, when used as an exogenous therapeutic, has been shown to be very effective in limiting inflammation in a diverse range of experimental models, including myocardial ischemia/reperfusion injury, arthritis, stroke, multiple sclerosis, and sepsis. Notably, this glucocorticoid-inducible protein, along with another anti-inflammatory mediator, lipoxin A(4), is starting to help explain and shape our understanding of the resolution phase of inflammation. In so doing, these molecules are carving the way for innovative drug discovery, based on the stimulation of endogenous pro-resolving pathways.