To date, most studies examining cell death during the development of osteoarthritis (OA) have focused on death of chondrocytes and have primarily examined advanced stages of the disease. Very good evidence suggests that chondrocyte death does occur at some point in the pathogenesis of OA and that it can be due to apoptosis, necrosis, or some combination of the two. Chondrocyte death can be induced by mechanical injury, loss of extracellular matrix, loss of growth factors, or excessive levels of reactive oxygen species. Although therapy specifically targeting cell death in human OA has not been reported, preclinical studies in animal models have provided early evidence that inhibition of caspases might slow OA-like changes in articular cartilage. Because of potential unwanted side effects from agents systemically inhibiting cell death, treatments specifically targeting cell death in OA will likely need to be delivered locally and in a manner that prevents systemic absorption. Inhibition of cell death in OA likely will not be a sole therapeutic target but rather a desired effect of interventions designed to reverse the catabolic-anabolic imbalance occurring in OA joint tissues.