New Findings What is the topic of this review? Genetic modifiers act on many different physiological aspects of muscle disease. Understanding and identifying such modifiers is important because their discovery may help to predict the course of muscle disease and also indicate pathways to be exploited in designing new therapeutics. What advances does it highlight? Genetic modifiers have been identified that act primarily on limb skeletal muscles. Newer modifiers, where the responsible gene has yet to be identified, alter the course of cardiopulmonary dysfunction in muscular dystrophy. Distinct modifiers that act differentially on limb skeletal muscles versus heart and respiratory muscles reflect underlying physiological differences of these muscle groups. Many single-gene disorders are associated with a range of symptoms that cannot be explained solely by the primary genetic mutation. Muscular dystrophy is a genetic disorder associated with variable outcomes that arise 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 harbours an insertion/deletion polymorphism in Ltbp4, the gene encoding latent transforming growth factor β binding protein 4. 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.