Acute inflammation constitutes a very well-organized response to any type of tissue damage engaging multiple systems such as the blood clotting mechanism, complement activation and the immune system, aiming in tissue repair and ultimately it's healing. Strenuous exercise is accompanied by muscle cell damage which is associated with inflammation (increase of cytokines, adhesion molecules, microparticles and neutrophils) in order to repair damaged tissues. It has been documented that acute exercise causes a biphasic leukocytosis consisting of an immediate and a delayed activation of lymphocytes, neutrophils, and macrophages. Free radicals generated by neutrophils and macrophages are vital in clearing away muscle tissue that has been damaged by exercise but they may also cause propagation of tissue damage. Neutrophils form the superoxide radical through the reaction of an enzyme called NADPH oxidase which is located in their plasma membrane. Although previous research has focused on the detrimental effects of free radicals (i.e. oxidative stress, aging, disease pathogenesis), there is mounting evidence now that free radicals may serve as useful signalling molecules to regulate cell growth, differentiation, proliferation, and death. Inflammation significantly changes cellular redox status by promoting a prooxidative response through immune cell infiltration to the damaged muscle cells while at the same time antioxidant adaptations permit the selective expression of antioxidant to keep the inflammatory response under control. Increasing evidence suggest that redox-sensitive signalling pathways, mainly NFkB, MAPK, and AP-1, have a prominent role in the regulation of muscle damage-induced inflammation through upregulation of both oxidative stress and antioxidants. In addition, homeostasis of reduced and oxidized glutathione (GSH:GSSG) appears to be crucial in redox signalling and overall control of the inflammation process. The present chapter examines the role of free radicals in redox signalling during exercise-induced inflammation and presents data regarding the potential role of long-term exercise training and antioxidant supplementation towards the protection against exercise-induced inflammation.