The extracellular matrix (ECM) is present in many load bearing structures like bone, cartilage, skeletal muscle, ligamens and tendons. As an example of an ECM rich tissue, tendons are designed to withstand considerable loads and it is shown that mechanical loading of tendon results in an up-regulation of collagen expression and an increased synthesis of collagen protein that is likely regulated by strain of the fibroblast. In vivo, the exercise stimulated increase in collagen formation peaks around 24 hrs and remains elevated for about 3 days after exercise. The degradation of collagen proteins also rises after exercise, but appears to peak earlier. The increase in collagen synthesis is regulated by growth factors like IGF-I, TGF-beta, estrogen and IL-6, most likely in an auto/paracrine fashion. This has been demonstrated both in vitro and in vivo. Fibroblasts from adult human tendon tissue is able to respond in an embryonic patters to induce fibrillogenesis in vitro. In addition to changes in collagen turnover, exercise also influences cross linking in the tendon structure, and some of these reactions appear faster than structural changes in collagen fibrils. Understanding how ECM adapts to mechanical loading will be the solution to unraveling the pathogenesis of connective tissue overuse and overload diseases like e.g. tendinopathy and ligament ruptures.