Joint tissues are exquisitely sensitive to their mechanical environment, and mechanical loading may be the most important external factor regulating the development and long-term maintenance of joint tissues. Moderate mechanical loading maintains the integrity of articular cartilage; however, both disuse and overuse can result in cartilage degradation. The irreversible destruction of cartilage is the hallmark of osteoarthritis and rheumatoid arthritis. In these instances of cartilage breakdown, inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor-alpha stimulate the production of matrix metalloproteinases (MMPs) and aggrecanases (ADAMTSs), enzymes that can degrade components of the cartilage extracellular matrix. In order to prevent cartilage destruction, tremendous effort has been expended to design inhibitors of MMP/ADAMTS activity and/or synthesis. To date, however, no effective clinical inhibitors exist. Accumulating evidence suggests that physiologic joint loading helps maintain cartilage integrity; however, the mechanisms by which these mechanical stimuli regulate joint homeostasis are still being elucidated. Identifying mechanosensitive chondroprotective pathways may reveal novel targets or therapeutic strategies in preventing cartilage destruction in joint disease. © 2010 New York Academy of Sciences.