Matrix metalloproteinases (MMPs) are a family of zinc-containing endo-proteinases that share structural domains but differ in substrate specificity, cellular sources, and inducibility. Macrophage production and secretion of large quantities of many MMPs, after contact with matrix proteins, is enhanced by surface determinants on activated T cells and suppressed by cytokines from Th1 and Th2 cells. T cells secrete predominantly the gelatinases MMP-2 and -9, after beta 1, integrin- or vascular cell adhesion molecule (VCAM)-1-dependent stimulation by cytokines and inflammatory mediators. MMPs of both T cells and macrophages facilitate secretion of TNF-alpha, by cleavage of the membrane-bound form. T cell MMPs prepare connective tissue matrices for T cell chemotaxis across basement membranes and through tissues. The greater amounts of diverse MMPs from macrophages are capable of degrading connective tissues, which may release stored growth factors. In limited studies of animal models of autoimmunity, specific MMP inhibitors have significantly decreased edema and inflammatory tissue damage, suggesting possible therapeutic benefits.