Neuregulin was described initially as a neurotrophic factor involved in the formation of the neuromuscular junction in skeletal muscle. However, in recent years, neuregulin has been reported to be a myokine that exerts relevant effects on myogenesis and the regulation of muscle metabolism. In this new context, the rapid and chronic metabolic effects of neuregulin appear to be related to muscle contraction. Indeed, the effects of neuregulin resemble those of exercise, which are accompanied by an improvement in insulin sensitivity. In this review, we challenge the classical role assigned to neuregulin in muscle and propound the emerging concept of its involvement in the regulation of energetic metabolism and insulin responsiveness.