Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting several joints. Proinflammatory cytokines (IL-1, IL-17, TNF-α and oncostatin M) activate multiple signalling pathways and transcription factors that augment matrix metalloproteinases (MMPs) and aggrecanases (ADAMTSs) expression. These events promote invasion of cartilage by proliferating pannus and ultimate loss of cartilage and bone. MMPs/ADAMTSs can be blocked at the levels of cytokines, signal transduction, transcription factors, mRNA translation and enzyme activity by the small-molecule synthetic and natural inhibitors including tissue inhibitors of metalloproteinases (TIMPs), specific ribozymes and by RNA interference. Overexpression of TIMP-1, TIMP-3 and TIMP-4 inhibits inflammation in RA-like animal models. TIMP-3 uniquely blocks aggrecanases and TNF-α converting enzyme (TACE/ADAM17) in vitro and could diminish synovial proliferation, its invasion of cartilage and inflammation in vivo. TIMP-3 knockout mice display enhanced inflammation and cartilage destruction. TIMPs are being engineered for therapeutic use to reduce RA synovial inflammation, pannus invasion of cartilage and tissue destruction. Because MMPs and aggrecanases inhibition may also interfere with their physiological functions of cytokine and growth factor processing, skeletal development, normal tissue remodelling and repair, extensive research on possible side effects of inhibitors is needed before their therapeutic use for RA. Nevertheless, multiple inhibitory strategies appear promising.