Abstract  Mast cells are present in nearly all vascularized tissues, but not the blood. They are best known for the prominent role they play in atopic disease. However, our current understanding of their direct and indirect roles in the immune response offers a more nuanced picture of both villain and hero. Although they are implicated in many inflammatory disorders, they also defend us from bacterial pathogens, prevent dangerous overreactions by the immune system, and even protect us from snake venom. Perhaps there is more to these maligned cells than we thought.