Mast cells are potent effectors of the inflammatory response, playing an important role in atopy, bacterial immunity, and animal models of arthritis, multiple sclerosis, and heart disease. Hence controlling mast cell numbers and responsiveness is essential for preventing inflammatory disease. This work demonstrated that the cytokine TGF-β1 is a potent inducer of mast cell apoptosis, a finding that was consistent for cultured mouse bone marrow-derived mast cells, peritoneal mast cells, and human mast cells. Cell death appeared to be the result of TGF-mediated repression of IL-3 receptor expression and function, leading to mitochondria1 damage and activation of an apoptotic cascade acting via p53 and caspases. While IL-3 receptor expression was reduced within one day of TGF-βl stimulation, apoptosis required at least 3 days to occur. This delay in onset is postulated to allow for protective mast cell effector functions, protecting the host from infection while preventing the establishment of chronic inflammation. These studies support the theory that TGF- β1 is an inhibitor of mast cell survival. Because of the widespread expression of TGF-β1, this cytokine may be an ideal candidate for control of mast cell homeostasis.