Tendinopathy affects millions of people in athletic and occupational settings and is a nemesis for patients and physicians. Mechanical loading is a major causative factor for tendinopathy; however, the exact mechanical loading conditions (magnitude, frequency, duration, loading history, or some combinations) that cause tendinopathy are poorly defined. Exercise animal model studies indicate that repetitive mechanical loading induces inflammatory and degenerative changes in tendons, but the cellular and molecular mechanisms responsible for such changes are not known. Injection animal model studies show that collagenase and inflammatory agents (inflammatory cytokines and prostaglandin E1 and E2) may be involved in tendon inflammation and degeneration; however, whether these molecules are involved in the development of tendinopathy because of mechanical loading remains to be verified. Finally, despite improved treatment modalities, the clinical outcome of treatment of tendinopathy is unpredictable, as it is not clear whether a specific modality treats the symptoms or the causes. Research is required to better understand the mechanisms of tendinopathy at the tissue, cellular, and molecular levels and to develop new scientifically based modalities to treat tendinopathy more effectively.