Skeletal muscle can undergo rapid growth in response to a sudden increase in work load. For example, the rat soleus muscle increases in weight by 40% within six days after the tendon of the synergistic gastrocnemius is sectioned. Such growth of the overworked muscle involves an enlargement of muscle fibers and occasional longitudinal splitting. Hypertrophy leads to greater maximal tension development, although decreased contraction time and reduced contractility have also been reported. Unlike normal developmental growth, work-induced hypertrophy can be induced in hypophysectomized or diabetic animals. This process thus appears independent of growth hormone and insulin as well as testosterone and thyroid hormones. Hypertrophy of the soleus can also be induced in fasting animals, in which there is a generalized muscle wasting. Thus muscular activity takes precedence over endocrine influences on muscle size. The increase in muscle weight reflects an increase in protein, especially sarcoplasmic protein, and results from greater protein synthesis and reduced protein breakdown. Within several hours after operation, the hypertrophying soleus shows more rapid uptake of certain amino acids and synthesis of phosphatidyl-inositol. By 8 hours, protein synthesis is enhanced. RNA synthesis also increases, and hypertrophy can be prevented with actinomycin D. Nuclear DNA synthesis also increases on the second day after operation and leads to a greater DNA content. The significance of the increased RNA and DNA synthesis is not clear, since most of it occurs in interstitial and satellite cells. The proliferation of the non-muscle cells seems linked to the growth of the muscle fibers; in addition, factors causing muscle atrophy (e.g. denervation) decrease DNA synthesis by such cells. In order to define more precisely the early events in hypertrophy, the effects of contractile activity were studied in rat muscles in vitro. Electrical stimulation enhanced active transport of certain amino acids within an hour, and the magnitude of this effect depended on the amount of contractile activity. Stimulation or passive stretch of the soleus or diaphragm also retarded protein degradation. Presumably these effects of mechanical activity contribute to the changes occuring during hypertrophy in vivo. However, under the same conditions, or even after more prolonged stimulation, no change in rates of protein synthesis was detected. These findings with passive tension in vitro are particularly interesting, since passive stretch has been reported to retard atrophy or to induce hypertrophy of denervated muscle in vivo. It is suggested that increased tension development (either passive or active) is the critical event in initiating compensatory growth.