The past decade has confronted us with a striking abundance of novel findings regarding the roles of mast cells in immune responses in health and disease. Newly developed models and techniques have enabled clear-cut dissection of the mast cell contribution in these settings. We now understand that mast cells possess critical effector functions not only within the traditional context of allergic reactions. It is likely that mast cells played pivotal roles in primitive immune systems, yet these functions have been masked in the recent eras by newer immune functions, such as adaptive immunity. Conceivably, mast cells should be refocused on so as to obtain new insights about diverse pathologic conditions, ultimately leading to novel therapeutic approaches targeting these fascinating cells.