Mast cells were discovered more than 100 years ago and until recently, have been considered renegades of the host with the sole purpose of perpetuating allergy. The discovery of mast cell–deficient mice that could be reconstituted with mast cells (the so called “mast cell knock‐in” mice) has allowed the study of the in vivo functions of mast cells and revealed several new facets of these cells. It is now evident that mast cells have a much broader impact on many physiological and pathologic processes. Mast cells, particularly through their dynamic interaction with the nervous system, have been implicated in wound healing, tissue remodeling, and homeostasis. Perhaps the most progress has been made in our understanding of the role of mast cells in immunity outside the realm of allergy, and host defense. Mast cells play critical roles in both innate and adaptive immunity, including immune tolerance. Greater insight into mast cell biology has prompted studies probing the additional consequences of mast cell dysfunction, which reveal a central role for mast cells in the pathogenesis of autoimmune disorders, cardiovascular disorders, and cancer. Here, we review recent developments in the study of mast cells, which present a complex picture of mast cell functions.