In the last decade, dramatic progress has been made in elucidating the molecular defects underlying a number of neuromuscular diseases. With the characterization of mutations responsible for muscle and nerve dysfunction in several inherited pathologies, and the identification of novel signaling pathways, in which subtle alterations can lead to significant defects in tissue metabolism, the field is poised to devise successful strategies for treatment of this debilitating and often fatal group of human ailments. Yet progress in therapeutic application has been slow despite our newly gained knowledge of basic biology. Hence, where direct therapeutic approaches to address the primary diseases are still sub-optimal, it may be more effective to focus on strategies for improving neuromuscular function. Among potential candidates, insulin-like growth factor (IGF-1) has been involved in several anabolic pathways in both skeletal muscle and the nervous system and it is a promising candidate to attenuate neuromuscular diseases. In this review, we will discuss the role of IGF-1 isoforms in neuromuscular diseases and the contribution of muscle-produced IGF-1 (mIGF-1) to motor neuron survival and activity.