High-resistance exercise training results in an increase in muscle wet mass and protein content. To begin to address the acute changes following a single bout of high-resistance exercise, a new model has been developed. Training rats twice a week for 6 wk resulted in 13.9 and 14.4% hypertrophy in the extensor digitorum longus (EDL) and tibialis anterior (TA) muscles, respectively. Polysome profiles after high-resistance lengthening contractions suggest that the rate of initiation is increased. The activity of the 70-kDa S6 protein kinase (p70^S6k), a regulator of translation initiation, is also increased following high-resistance lengthening contractions (TA, 363 ± 29%; EDL, 353 ± 39%). Furthermore, the increase in p70^S6k activity 6 h after exercise correlates with the percent change in muscle mass after 6 wk of training (r = 0.998). The tight correlation between the activation of p70^S6k and the long-term increase in muscle mass suggests that p70^S6k phosphorylation may be a good marker for the phenotypic changes that characterize muscle hypertrophy and may play a role in load-induced skeletal muscle growth.