Mutations in myostatin (GDF8) cause marked increases in muscle mass, suggesting that this transforming growth factor‐β (TGF‐β) superfamily member negatively regulates muscle growth. Myostatin blockade therefore offers a strategy for reversing muscle wasting in Duchenne's muscular dystrophy (DMD) without resorting to genetic manipulation. Here, we demonstrate that pharmacological blockade using a myostatin propeptide stabilized by fusion to IgG‐Fc improved pathophysiology of the mdx mouse model of DMD. Functional benefits evidenced by specific force improvement, exceeded those reported previously using myostatin antibody‐mediated blockade. More importantly, use of a propeptide blockade strategy obviates possibilities of anti‐idiotypic responses that could potentially limit the effectiveness of antibody‐mediated myostatin blockade strategies over time. This study provides a novel pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD and since it uses an endogenous inhibitor of myostatin should help circumvent technical hurdles and toxicity associated with conventional gene or cell based therapies. FASEB J. 19, 543–549 (2005)