Joint injury results in cartilage lesions that are characterized by a poor repair response, and such lesions often progress to osteoarthritis. Acute joint injury or chronic exposure of cartilage to an abnormal biochemical or biomechanical environment results in the activation of chondrocytes. This chondrocyte response is manifested by enhanced cell proliferation and death, matrix degradation, and new matrix synthesis. Cytokines are important stimuli of this chondrocyte activation response and trigger joint inflammation that can accompany cartilage injury. The presence of cytokines in cartilage is associated with abnormal extracellular matrix remodeling and loss, therefore defining them as a class of targets for therapeutic interventions. Insight into intracellular signaling mechanisms that are activated by cytokines may provide the basis for pharmacologic interventions that promote cartilage repair.