Mast cells are highly effective sentinel cells, found close to blood vessels and especially common sites of potential infection, such as the skin, airways and gastrointestinal tract. Mast cells participate actively in the innate immune responses to many pathogens through a broad spectrum of mediators that can be selectively generated. They also have a role as innate effector cells in enhancing the earliest processes in the development of acquired immune responses. Studies of bacterial and parasitic models have revealed mast cell dependent regulation of effector cell recruitment, mucosal barrier function and lymph node hypertrophy. An important role for mast cells in viral infection is also implied by several in vivo and in vitro studies. There are multiple direct and indirect pathways by which mast cells can be selectively activated by pathogens including Toll-like receptors, co-receptors and complement component receptors. Understanding the mechanisms and scope of the contribution of mast cells to host defence will be crucial to regulating their activity therapeutically.