The chapter discusses the role of matrix metalloproteinases (MMPs) in the destruction of cartilage, tendon, and bone in rheumatoid arthritis (RA) and osteoarthritis (OA). MMPs are enzymes that degrade the extracellular matrix, and their overexpression in these diseases leads to irreversible joint destruction. The collagenases MMP-1 and MMP-13 are particularly important in collagen degradation, while other MMPs like MMP-2, MMP-3, and MMP-9 degrade non-collagen matrix components. The chapter also explores the regulation of MMP gene expression through various signaling pathways, including AP-1, NF-κB, and TGF-β. Efforts to develop inhibitors of MMP activity and synthesis have been ongoing, but no effective clinical inhibitors currently exist. The chapter highlights the potential of using crystal structures of MMPs and signal transduction pathways to develop more targeted therapeutics. Despite the challenges, there is optimism that advancements in molecular medicine will lead to better treatments for arthritis.The chapter discusses the role of matrix metalloproteinases (MMPs) in the destruction of cartilage, tendon, and bone in rheumatoid arthritis (RA) and osteoarthritis (OA). MMPs are enzymes that degrade the extracellular matrix, and their overexpression in these diseases leads to irreversible joint destruction. The collagenases MMP-1 and MMP-13 are particularly important in collagen degradation, while other MMPs like MMP-2, MMP-3, and MMP-9 degrade non-collagen matrix components. The chapter also explores the regulation of MMP gene expression through various signaling pathways, including AP-1, NF-κB, and TGF-β. Efforts to develop inhibitors of MMP activity and synthesis have been ongoing, but no effective clinical inhibitors currently exist. The chapter highlights the potential of using crystal structures of MMPs and signal transduction pathways to develop more targeted therapeutics. Despite the challenges, there is optimism that advancements in molecular medicine will lead to better treatments for arthritis.