Myostatin is a secreted protein that acts as a negative regulator of skeletal muscle mass. During embryogenesis, myostatin is expressed by cells in the myotome and in developing skeletal muscle and acts to regulate the final number of muscle fibers that are formed. During adult life, myostatin protein is produced by skeletal muscle, circulates in the blood, and acts to limit muscle fiber growth. The existence of circulating tissue-specific growth inhibitors of this type was hypothesized over 40 years ago to explain how sizes of individual tissues are controlled. Skeletal muscle appears to be the first example of a tissue whose size is controlled by this type of regulatory mechanism, and myostatin appears to be the first example of the long-sought chalone.