Muscular dystrophy presents a formidable challenge for gene therapy. Major hurdles include the need to correct large masses of tissue (40% of the body weight) with minimal damage to the already inflamed and necrotic muscles, absence of immune rejection of the therapeutic protein, and sustained (if possible, life-long) expression. Plasmid DNA has long been neglected as a candidate vector for this devastating disease, due to a low in vivo transfection efficiency. It, nevertheless, meets many of the prerequisites for a clinically viable treatment: ease of manufacturing, low toxicity, immunologically innocuous (to allow repeated administrations and insensitivity to pre-existing immunity), and accommodation of the large 11-kb dystrophin cDNA. Over the past year, interest has increased with two major breakthroughs: the first gene-based clinical trial for Duchenne muscular dystrophy that involved a human dystrophin plasmid, and a new method of intravascular delivery showing widespread transfection of limb muscles in large animals, including non-human primates. This opens a new avenue for the treatment of Duchenne dystrophy and many applications using gene delivery to skeletal muscle.