Rotator cuff tendon and muscle can beneficially adapt to exercise, but it is unknown how acute responses following a single bout of exercise lead to chronic, beneficial adaptations. To develop new prevention and treatment strategies for overuse injuries, we must first characterize how tissues adapt to non-injurious loading. One feature that may distinguish beneficial and detrimental responses are pathways associated with inflammation and tissue healing, including activation of the arachidonic acid cascade and matrix turnover facilitated by matrix metalloproteinases (MMPs). The objective of this dissertation was to characterize temporal, acute and chronic responses of the rat supraspinatus to non-injurious exercise and examine the roles of cyclooxygenases-1 and -2 (arachidonic acid cascade components) and MMPs in governing these responses by using pharmacologic inhibition. Using a rat model of non-injurious exercise, we showed that tendon adapted chronically by enhancing its mechanical properties. Following a single bout of exercise, tendon showed mild trends toward reduced mechanical properties, which may initiate the beneficial adaptations detected chronically. Exercised tendon also had decreased MMP activity. We administered ibuprofen, an inhibitor of cyclooxygenases-1 and -2, to understand how this commonly used over-the-counter drug affects muscle and tendon responses to exercise. Ibuprofen did not detrimentally affect tendon mechanical properties but did result in decreased muscle fiber cross-sectional area. Taken together, these findings imply that the arachidonic acid cascade is not a primary modulator of tendon adaptations to non-injurious exercise but is important for muscle growth. Finally, we studied the effects of doxycycline, a broad-spectrum MMP inhibitor, on supraspinatus muscle and tendon adaptations to exercise. Doxycycline enhanced tendon mechanical properties and collagen organization from sedentary animals but not in exercised animals, which supports the increased MMP activity detected in sedentary tendons. Doxycycline reduced muscle fiber cross-sectional area specific to exercised animals. We conclude that the pathways responsible for muscle and tendon adaptations to exercise may be tissue-dependent, and drugs such as ibuprofen and doxycycline also have activity-dependent effects. These studies provide a foundation for future work to develop more efficient physical training regimens and new prevention, treatment, and rehabilitation modalities for overuse injuries.