Mast cells (MCs) were once considered only as effector cells in pathogenic IgE- and IgG-mediated responses such as allergy. However, developments over the last 15 years have suggested that MCs have evolved in vertebrates as beneficial effector cells that are involved in the very first inflammatory responses generated during infection. This pro-inflammatory environment has been demonstrated to be important for initiating innate responses in many different models of infection and more recently, in the development of adaptive immunity as well. Interestingly this latter finding has led to the discovery that small MC-activating compounds can behave as adjuvants in vaccine formulations. Thus, our continued understanding of the MC in the context of infectious disease is likely to not only expand our scope of the MC in the normal processes of immunity, but provide new therapeutic targets to combat disease.