The popular view that all lipid mediators are pro-inflammatory arises largely from the finding that nonsteroidal anti-inflammatory drugs block the biosynthesis of prostaglandins. The resolution of inflammation was widely held as a passive event until recently, with the characterization of novel biochemical pathways and lipid-derived mediators that are actively turned on in resolution and that possess potent anti-inflammatory and proresolving actions. A lipid-mediator informatics approach was employed to systematically identify new families of endogenous local-acting mediators from omega-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) in resolving exudates, which also contain lipoxins and aspirin-triggered lipoxins generated from arachidonic acid. Given their potent bioactions, these new chemical mediator families were termed resolvins and protectins. Here, we review the recent advances in our understanding of the biosynthesis and stereospecific actions of these new proresolving mediators, which have also proven to be organ protective and antifibrotic.