Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by the destruction of joint tissues including cartilage and bone. Cartilage degradation is attributed to metalloproteinases (MPs) that belong to matrix metalloproteinase family and a disintegrin and metalloprotease with thrombospondin type 1 motifs produced by inflamed joint tissues. In addition, an enzyme that belongs to a disintegrin and metalloprotease family is also involved in release of inflammatory cytokines. Several highly selective inhibitors have been developed for MPs thought to play a role in RA pathogenesis and examining these inhibitors as potential drugs is becoming realistic. This chapter discusses recent reports on MPs in RA and their potential as a therapeutic target.