Osteoarthritic joint disease is characterized by the progressive loss of articular cartilage resulting in functional impairment, pain and discomfort. The major components in cartilage, collagen and aggrecan, are lost during disease through the action of degradative proteolytic enzymes. The proteases responsible for aggrecan degradation are termed aggrecanases. The aggrecanases represent a family of enzymes with great therapeutic potential as targets for the treatment of osteoarthritis. Here we review the family of aggrecanases and the progress made toward the identification of potent and selective enzyme inhibitors for use as therapeutic agents.