Journal of Signal Transduction activated or modulated by ROS contribute to further com- plicate this scenario. Thus, a gradual and variable, rather than a sharp, boundary is likely to characterize the transition between the two types of ROS actions. Such a variable “greyscaling” of ROS eﬀects may depend on extrinsic and intrinsic situations such as, at least, (i) the concentration of ROS, (ii) the type of reactive species involved, (iii) the persistence of ROS activity, (iv) the localization of ROS source, (v) the antioxidant capacity and the energy status of muscle cells, (vi) their ability to adapt to oxidative stress (which in vivo also depends on ageing and/or physical train- ing), (vii) the diﬀerentiative status, for example, myoblasts versus integrated myotubes, (viii) the absence/presence of an inﬂammatory process, and (ix) the plasticity of the signaling pathways triggered/aﬀected by ROS. The balance between these factors will ultimately determine which type of signal(s) and eﬀect(s) will prevail within the cell. Again, the hormetic nature of ROS emerges as the key feature of these species in many tissues, including skeletal muscle. Careful titration of ROS levels within skeletal muscle cell may therefore lie at the cross between the initiation and progression of disease and cell death, the induction of mitochondrial biogenesis, repair, and more generally cellular metabolic health. Supplementation with exogenous antioxi- dants is being widely studied to attain and maintain an “ideal titration” of ROS within skeletal muscle: unfortunately, at the present, no clear indication of the beneﬁts arising from supplemental antioxidant intake emerges from literature. This reﬂects the need for further studies aimed at clarifying how to regulate ROS levels to exploit their physiological eﬀects and avoid their damages. 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