Many single gene disorders are associated with a range of symptoms that cannot be solely explained by the primary genetic mutation. Muscular dystrophy is a genetic disorder associated with variable outcomes that arises from both the primary genetic mutation and the contribution from environmental and genetic modifiers. Disruption of the dystrophin complex occurs in Duchenne muscular dystrophy and limb girdle muscular dystrophy producing heart and muscle disease through a cellular injury process characterized by plasma membrane disruption and fibrosis. Multiple modifier loci have been mapped by using a mouse model of muscular dystrophy. These modifiers exert their effect often on specific muscle groups targeted by the muscular dystrophy process, possibly reflecting distinct pathophysiological processes among muscle groups. Genetic modifiers act on both cardiac and respiratory muscle parameters suggesting genetic and physiological integration of cardiopulmonary function. Skeletal muscles of the limbs are modified by a locus on mouse chromosome 7. This region of chromosome 7 harbors an insertion/deletion polymorphism in Ltbp4, the gene encoding latent TGFβ binding protein. Ltbp4 exerts its effect in muscle disease by acting on plasma membrane stability and fibrosis, thereby linking instability of the sarcolemma directly to fibrosis. In the human muscle disease Duchenne Muscular Dystrophy, protein coding single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation demonstrating that modifiers identified from mouse studies translate to human disease.