The dystrophin glycoprotein complex (DGC) is a large multisubunit complex located throughout the sarcolemma of striated muscle fibers. This complex is critical for maintaining the structural integrity of muscle fibers during muscle contraction and also provides a scaffold for signaling molecules. Defects in some components of the DGC, such as dystrophin and sarcoglycans, disrupt the complex and lead to muscular dystrophies. Alpha-dystrobrevin is a dystrophin-related component of the DGC that is localized to the cytoplasmic side of the sarcolemma. In skeletal muscle, alpha-dystrobrevin is also highly concentrated at the neuromuscular junction, a highly specialized region of the sarcolemma responsible for receiving motor nerve signals necessary for muscle contraction. Current evidence suggests that alpha-dystrobrevin plays an important role in signaling at the sarcolemma and in the maturation and maintenance of the postsynaptic apparatus at the neuromuscular junction. In this review, we summarize the currently known cellular and molecular properties of alpha-dystrobrevin in skeletal muscle and discuss its potential functions at both the sarcolemma and neuromuscular junction.