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Uncontrolled inflammation giving rise to excessive tissue inflammation can lead to chronic inflammation that enhances tissue destruction, amplifying many chronic human pathologies. Normally the acute inflammatory response is protective and should be self-limited returning tissues to functional homeostasis with endogenous programmed resolution via leukocyte vasculature cell-cell interactions and crosstalk that biosynthesize pro-resolving mediators. When failed resolution takes place, as with the use of NSAIDs, tissues undergo chronic inflammation and fibrosis. Herein, we discuss these mechanisms and the role of specialized proresolving mediators, the resolvins, protectins and maresins produced from essential omega-3 fatty acids EPA and DHA, and their contributions via their cognate cell surface receptors, to the resolution response. Harnessing these pathways and their cellular mechanisms can help in providing new therapeutic approaches to many human diseases, infections, organ protection and trauma via resolution medicine to enhance the body’s own resilience to challenge.