Summary: Increasing evidence suggests that mast cells (MCs), in addition to acute allergic reactions, are involved in the pathogenesis of chronic inflammatory diseases and in particular in rheumatoid arthritis (RA). MCs reside in connective tissues and in synovial tissue of joints. They produce an array of proinflammatory mediators, tissue destructive proteases, and cytokines, most prominently tumor necrosis factor-α, which is one of the key cytokines in the pathogenesis of RA. MCs may also participate in the development of secondary or amyloid A amyloidosis, as the partial degradation of the serum amyloid A (SAA) protein by MCs leads to the generation of a highly amyloidogenic N-terminal fragment of SAA. MCs may contribute to the pathogenesis of connective tissue diseases, scleroderma, vasculitic syndromes, and systemic lupus erythematosus, although the data available are limited. Inhibition of the most important growth factor receptor of human MCs, c-Kit, by the selective tyrosine kinase inhibitor imatinib mesylate, induces apoptosis of synovial tissue MCs. As MCs are long-lived cells, induction of their apoptosis could be a feasible approach to inhibit their functions. Preliminary findings suggest that a drug that inhibits c-Kit could have anti-rheumatic activity in the treatment of patients with RA and spondyloarthropathies.