Matrix metalloproteinases (MMPs), A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) are zinc-dependent endopeptidases that play a critical role in the destruction of extracellular matrix proteins and, the shedding of membrane-bound receptor molecules in various forms of arthritis and other diseases. Under normal conditions, MMP, ADAM and ADAMTS gene expression aids in the maintenance of homeostasis. However, in inflamed synovial joints characteristic of rheumatoid arthritis and osteoarthritis. MMP, ADAM and ADAMTS production is greatly increased under the influence of pro-inflammatory cytokines. Analyses based on medicinal chemistry strategies designed to directly inhibit the activity of MMPs have been largely unsuccessful when these MMP inhibitors were employed in animal models of rheumatoid arthritis and osteoarthritis. This is despite the fact that these MMP inhibitors were largely able to suppress pro-inflammatory cytokine-induced MMP production in vitro. A focus on ADAM and ADAMTS inhibitors has also been pursued. Thus, recent progress has identified the "sheddase" activity of ADAMs as a viable target and the development of GW280264X is an experimental ADAM17 inhibitor. Of note, a monoclonal antibody, GLPG1972, developed as an ADAMTS-5 inhibitor, entered a Phase I OA clinical trial. However, the failure of many of these previously developed inhibitors to move beyond the preclinical testing phase has required that novel strategies be developed that are designed to suppress both MMP, ADAM and ADAMTS production and activity.