Osteoarthritis is a painful and debilitating disease of the joints that is characterized by progressive degeneration of the articular cartilage that lines the joint surfaces. The etiology of osteoarthritis is poorly understood, although it is now well accepted that biomechanical factors play an important role in the onset and progression of this disease. The primary goal of our studies has been to determine the mechanisms by which mechanical loading affects the physiology of our joints. Using a hierarchical approach to span different systems ranging from clinical studies and in vivo animal models to studies of tissue, cellular, and subcellular mechanics, we have identified specific mechanical signaling pathways that appear to play a role in cartilage physiology as well as pathology. These pathways may provide novel pharmacologic targets for the modification of inflammation or cartilage degeneration in osteoarthritis. Additionally, our studies have focused on tissue engineering approaches for repairing cartilage damage with osteoarthritis. Using novel textile processes that allow weaving of biomaterial fibers in three dimensions, we have created functionalized bioactive scaffolds that can recreate many of the complex biomechanical properties and anatomic features of articular cartilage. In combination with a multipotent population of stem cells isolated from subcutaneous fat, we have developed a tissue-engineering approach for resurfacing osteoarthritic joint surfaces. Taken together, these studies emphasize the critical role that biomechanics plays in the physiology as well as pathology of the joint, and demonstrate the importance of biomechanical factors in functional tissue engineering of cartilage and other joint tissues.