Uncontrolled inflammation is now known to be a component of many of the widely occurring chronic diseases such as arthritis, periodontal disease, asthma, cardiovascular diseases and neurodegenerative diseases. Using a systems approach with self-limited inflammatory infectious exudates to map tissue events, cell traffic and identification of protein and chemical mediators, we identified 3 structurally separate families of potent n-3 essential fatty acid-derived (EPA, DPA, DHA) novel mediators, termed resolvins, protectins and maresins.  Complete structural elucidation and total organic synthesis of these new molecules demonstrated their functions in vivo in the resolution of acute inflammation in many animal models. Each member of this super-family is chemically distinct and functions as a pro-resolving local mediator that controls the duration and magnitude of acute inflammatory responses with actions in pico- to nanogram range in animal disease models. The biosynthetic pathways and potent mediators from the resolvin, protectin and maresin bioactive metabolomes are coined specialized pro-resolving mediators (SPM). Mapping of these resolution circuits provides new avenues to probe the molecular basis of many widely occurring diseases (CN Serhan, Nature 2014)¹. This presentation shall focus on our recent advances in the biosynthesis and functions of specialized pro-resolving mediators (SPM), stereochemical assignments, total organic synthesis of new resolvins, SPM and their actions in counter-regulation of pro-inflammatory cytokines (TNFa, IL-6) and pro-inflammatory eicosanoids. SPM possess potent multi-pronged anti-inflammatory, pro-resolving, and anti-microbial actions in animal models. We use LC-MS-MS mediator-metabololipidomics to profile SPM in human tissues (serum, plasma², breast milk³, adipose and brain) uncovering new pathways that stimulate tissue regeneration and bacterial clearance^4-6. Several SPM are in clinical development and in ongoing clinical trials in humans. Identification of SPM during self-limited inflammations resolution phase indicates that resolution is an active programmed process challenging the old concept that resolution is a passive process where chemotactic molecules dilute and simply wane to resolve the local leukocyte exudates. Together these findings indicate that endogenous resolution pathways may underlie prevalent diseases associated with uncontrolled inflammation and open the potential for resolution-based pharmacology.