Over the past decade, the enigmatic pathogenic mechanisms of the most common forms of muscular dystrophy have been defined. In this report, the molecular defects for each of these disorders are fully described, demonstrating the potential for therapeutic intervention. In facioscapulohumeral muscular dystrophy, recent findings implicate a stabilized DUX4 transcript within the contracted D4Z4 repeats, opening the door for an RNA interference treatment strategy. In the myotonic dystrophies (dystrophica myotonia [DM]), two variants of the disease (DM1 and DM2) are caused by unrelated genes yet manifest overlapping phenotypes. The common mechanism is a splicing disorder related to RNA toxicity. Duchenne muscular dystrophy is the most common childhood form of muscular dystrophy. In many ways, the molecular gene defects are the most traditional. Gene repair strategies have advanced to the level of clinical testing, and we hope they will provide relief for this most devastating form of muscular dystrophy.