Resolution of inflammation plays an important part in maintaining homeostasis. It is an actively programmed progress involving multiple immune cells and mediators. Specialized pro-resolving mediators (SPMs) derived from Ω-3 polyunsaturated fatty acids include resolvins, protectins and maresins, and they exert abilities in the resolution of inflammation, host defense, organ protection, and tissue generation. Periodontitis is an inflammatory and destructive disease in the periodontal tissue initiated by dental plaque. Inadequate proinflammatory or proresolving responses, or the imbalance between the two, may contribute to the pathogenesis of the disease. Studies have shown that activating specialized receptors SPMs displayed multiple biological effects towards periodontitis, including resolution of inflammation, alveolar bone protection, periodontal tissue regeneration, and pathogen resistance. Thus, the relationship between SPM and periodontitis and the potentials and challenges in SPM application were reviewed.