The sudden and systemic activation of mediator release from mast cells and basophils that can occur when some sensitized subjects are challenged by minute amounts of specific antigen (eg, from an insect sting or peanuts) can result in fatal anaphylaxis, a reaction that arguably represents the most grotesque imbalance between the cost and benefit of an immune response. Why then do mast cells and basophils continue to exist and, in the case of mast cells, populate almost all vascularized tissues? This review will consider the roles of mast cells and basophils in health and disease, emphasizing particularly their proven or potential functions in host defense. We will also describe briefly some approaches to investigate mast cell and basophil functions in vivo, including the use of mast cells generated directly from embryonic stem cells in vitro.