Metalloproteinases that degrade extracellular matrix molecules play important roles in development and progression of various diseases. Among them, collagenases are unique as they have an ability to degrade triple helical interstitial collagens into 3/4 and 1/4 fragments, a crucial step for collagenolysis in the tissue. Collagenases, consisting of a catalytic domain and a hemopexin domain, requires both domains for collagenolysis. The enzymes unwind triple helical collagen before they hydrolyze the peptide bonds. Aggrecanases are also multidomain metalloproteinases belonging to the ADAMTS family, and the noncatalytic ancillary domains also play an important role in recognition of aggrecan and their activities. Attenuation of collagenase and aggrecanase activities will be achieved by inhibitors or antibodies that interact directly with those noncatalytic ancillary domains (exosite inhibitors). Such molecules will be attractive for therapy as they will be highly selective because they are based on the unique mechanism of each proteinase.