Advances on mechanisms in resolution of acute inflammation uncovered a new genus of pro-resolving lipid mediators that include separate families of molecules: lipoxins, resolvins, protectins and maresins, collectively coined specialized pro-resolving mediators (SPM). Synthetic SPM possess potent bioactions when administered in vivo. In animal experiments, SPM evoke anti-inflammatory and novel pro-resolving mechanisms as well as enhance microbial clearance. While identified in inflammation-resolution, SPM are conserved structures with functions also in host defense, pain, organ protection and tissue remodeling. This review covers SPM mechanisms and new omega-3 essential fatty acid pathways that open a path for physiologic functions.