|Experts from different fields study the development of Musculoskeletal Disorders (MSDs) from different perspectives: epidemiologists identify potential MSD risk factors, traditional ergonomists analyze motions, and medical doctors remedy the pain and sickness symptoms by prescribing medicine, rehabilitation programs, and surgeries. However, an integrated understanding of the injury mechanism of MSDs, especially the early developmental stages, is not well established. Accurate and precise quantitative estimation of exposure to specific risk factors is essential for evaluating worker risk, measuring effectiveness of ergonomic interventions in order to promote worker health and well-being. One commonly prescribed method of MSD prevention and intervention, rest, has been identified of significant healing and recovery value. In sufficient rest, on the other hand, is identified as a potential significant MSD risk factor. However, the scheduling of work-rest cycles at manufacturing sites is often oriented towards meeting production goals and rarely takes MSD prevention of the workers into consideration. Current literature provides little information for the dose-response relationship between duration and frequency of rest breaks during work-rest cycles or between work-shifts and musculoskeletal injury formation and recovery outcomes. Relevant applicable experiment schemes have not been established to quantify the effect of rest in different stages of MSD development and recovery. This dissertation was designed to address these issues and expand upon the current scientific literature regarding the impact of rest and secondary intervention on MSD development and recovery. Manufacturing work shifts and work-rest cycles were simulated to induce musculoskeletal injuries; human and animal experiment models were developed to complement each another in order to quantify physiological, behavioral and biological outcomes of the injuries and recovery over repeated work-rest cycles. Previous studies that adopted similar animal models have demonstrated significant translational value of these models in reflecting human MSD injury pathways. Three specific aims were met through three studies, all under the rest versus MSD development and recovery theme. The study described in Chapter Three studied human subjects’ muscle damage biomarker Creatine Kinase’s fluctuating levels post repeated bouts of eccentric exercise of either high or low loading levels and taking either long but infrequent or short but frequent rest breaks between equal total workload. We found that short but frequent rest breaks were associated with greater muscle damage. The second study described in Chapter Four developed a forced downhill treadmill running model for rats to study physiological adaptation, systemic inflammation, stress, and tissue pathology as outcomes of chronic eccentric exertion with either long but infrequent or short but frequent rest breaks when total workload was equal. We found that rats that followed different work-rest schedules expressed significant difference in physiological adaptations and stress responses. Rats that followed long but infrequent rest scheduling might have experienced greater body weight as well as oxidative stress fluctuations in comparison with ones that followed short but frequent rest scheduling, although both working groups experienced significant deficit in body weight during the experiment period as well as significant pathological changes in Achilles tendon. The third study described in Chapter Five examined effectiveness of flat treadmill running, a common secondary intervention for MSDs, and rest on rats’ task performance, pain behaviors, systemic inflammation, and tissue pathology during and post exposure of high repetition, high force (HRHF) upper extremity tasks over 14 weeks. Six treatment groups: (1) food restricted control (FRC); (2) trained to high force and euthanized (TRHF); (3) trained to high force and rested (TRHF+Rest); (4) trained to high force, rested and ran on treadmill (TRHF+Rest+TM); (5) trained then performed the HRHF task (10wk HRHF); (6) trained, performed the HRHF task and ran on treadmill (10wk HRHF+TM). We did not find treadmill exercise at the chosen speed effective in remedying the rats’ voluntary task performance, reflexive grip strength, or mechanical allodynia induced by the high repetition high force reaching task. Instead treadmill running had opposite effects on functional outcomes, likely due to nerve inflammation and pain occurred during HR training, not recovering during rest, becoming more expressed during HRHF task and even worse when treadmill running was prescribed together with the HRHF task. We found that rest attenuated the mechanical sensitivity and systemic inflammation, remedied tendon’s morphological changes, yet did not improve the rats’ grip strength. Overall, these findings hold great promise for future development of guidelines to manufacturing work-rest scheduling in a manner that protects worker’s health and well-being while maintains productivity. They also add to the body of existing knowledge of MSD development and recovery mechanism, which can be expanded to meaningful clinical applications and can contribute to ergonomic assessment design and refinement.