The repair of articular cartilage following papain injection into the knee joint of the guinea pig was studied by light and electron microscopy, as well as by autoradiography using tritiated thymidine. Papain injection rapidly produced complete degradation of cartilage proteoglycan. Although a number of chondrocytes were also destroyed, the remaining chondrocytes showed mitotic cell division with resultant formation of cell clusters. Such chondrocytic regeneration, however, did not contribute significantly to the repair of cartilage tissue. On the other hand, mesenchymal cells proliferated from the transition zone and extended over the surface of the damaged cartilage. At the peripheral portion of the articular surface, they migrated and differentiated into chondrocytes with the formation of abundant intercellular matrix to produce hyaline cartilage. From these findings, it was apparent that mesenchymal cells in the transition zone were actively engaged in the repair of articular cartilage.