In healthy cartilage, effective weight-bearing requires a high concentration of intact aggrecan. Degradation and loss of aggrecan are features of osteoarthritis (OA). It is unclear whether ADAMTS-4, ADAMTS-5, or both of these aggrecanases from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzyme family, are responsible for aggrecanolysis in human OA, and at what stage of disease these enzymes are active. Several potential disease-modifying agents for OA include glucosamine and chondroitin sulfate, diacerhein, and pentosan polysulfate; although their mechanisms of action in vivo are unknown, data from in vitro studies and animal models suggest that their efficacy might be partly due to inhibition of proinflammatory pathways that lead to downregulation of ADAMTS enzymes. Some histone deacetylase inhibitors that are successfully used to treat cancer can block ADAMTS-5 expression; however, these inhibitors will only be considered as potential therapies for OA if their toxicity is markedly reduced. ADAMTS inhibitors currently in development are expected to show excellent specificity now that crystal structures for several ADAMTS enzymes are available to guide drug design. ADAMTS-4 and ADAMTS-5 are appropriate targets for OA therapies, but ultimately, inhibitors of these enzymes will form only part of a larger arsenal of therapies.