Among other factors, articular cartilage degeneration is caused by proteolytic enzymes. Different cell types of the synovial fluid and/or the synovial membrane and cartilage release specific proteases. Normally, these are finely tuned with their inhibitors. When this balance is altered, the proteolytic action may prevail, producing tissue damage, cartilage disruption, and ultimately a full osteoarthritic picture. The protease antiprotease mechanism opens new perspectives in the diagnosis and pharmacologic management of osteoarthritis. Early diagnosis and improved monitoring of the evolution of the disease are made possible, and a more rational therapy against cartilage disruption becomes feasible.