Calpain 3 is a 94‐kDa calcium‐dependent cysteine protease mainly expressed in skeletal muscle. In this tissue, it localizes at several regions of the sarcomere through binding to the giant protein, titin. Loss‐of‐function mutations in the calpain 3 gene have been associated with limb‐girdle muscular dystrophy type 2A (LGMD2A), a common form of muscular dystrophy found world wide. Recently, significant progress has been made in understanding the mode of regulation and the possible function of calpain 3 in muscle. It is now well accepted that it has an unusual zymogenic activation and that cytoskeletal proteins are one class of its substrates. Through the absence of cleavage of these substrates, calpain 3 deficiency leads to abnormal sarcomeres, impairment of muscle contractile capacity, and death of the muscle fibers. These data indicate a role for calpain 3 as a chef d'orchestre in sarcomere remodeling and suggest a new category of LGMD2 pathological mechanisms.