Using a systems approach to profile self‐limited inflammatory exudates, we identified three novel families of lipid‐derived mediators, coined the resolvins, protectins and most recently, the maresins that control both the magnitude and duration of inflammation. The mapping of these endogenous resolution circuits provides new avenues to probe the molecular basis of many widely occurring inflammatory diseases. This article focuses on our recent advances on the functional metabolomics of this novel genus of specialized pro‐resolving mediators (SPM). SPM include resolvins, protectins and maresins and are biosynthesized from essential omega‐3 fatty acid precursors. Each possesses potent multi‐pronged actions that proved to be stereoselective with human cells and in animal disease models. Resolvins and protectins are also produced in bone marrow. Together, these findings suggest that defective resolution mechanism(s) may underlie some chronic inflammatory diseases. Moreover, identification of functional SPM biosynthesized during inflammation‐resolution indicates that resolution is an active process.