Skeletal muscle is an essential organ for the motor functions and its defects are associated with functional impairments of other organs including brain. Muscle contraction is the fundamental skeletal muscle function and is strictly controlled by motor neuron, which requires neuromuscular junction (NMJ), a chemical synapse between motor nerve terminal and myotube (myofiber). Defects in NMJ cause various functional abnormalities of skeletal muscle including muscle weakness. This review presents an overview of the current understanding of signaling in NMJ formation and maintenance in skeletal muscle and the development of NMJ-targeted therapeutics.