Creatine (Cr) - along with the Cr kinase (CK) system - plays a fundamental role in muscle biochemistry and physiology not limited to its ergogenic role. Indeed, Cr has been shown to exert pleiotropic effects, which promote protein accretion, muscle-specific protein synthesis, growth in cultured myogenic cells and favour the myogenic process either in normal or stressing conditions. This review focuses on the effects of Cr supplementation on cellular and mitochondrial biochemistry and function in the course of skeletal muscle differentiation, either in normal or oxidatively stressing conditions, and on the ensuing nutraceutical/therapeutic perspectives.