Physical exercise induces a network of alterations in the transcriptome and proteome of the skeletal muscle, resulting in modifications of the muscle physiology. Intriguingly, exercise also transiently induces the production of both reactive oxygen species (ROS) and some inflammatory cytokines in skeletal muscle. In fact, it seems that exercise-induced ROS are able to stimulate cytokine production from skeletal muscle. Despite the initial view that ROS were potentially cell damaging, it now seems possible that these substances have important roles in the regulation of cell signaling. Muscle-derived cytokines, so-called 'myokines', are distinguished from inflammation and instead possess important anti-inflammatory and metabolic properties. In this opinion piece, we suggest that both ROS and myokines are important players in muscle adaptation to exercise.