Histamine was first recognized as a primary mediator in anaphylactic responses triggered by mast cells. Antagonists of the H1 subtype of histamine receptors remain clinically significant as antiallergic drugs. While mast cells have been well recognized for their roles in inflammatory diseases, such as immediate-type allergies and urticaria, our understanding of their physiological role has not been entirely sufficient. The recent development of excellent mouse models with genetically deficient mast cells has paved the way for identifying novel physiological functions of these cells. Mast cells are distributed across nearly all vascularized tissues in the body, and histamine receptors are ubiquitously expressed. Thus, it is anticipated that further discoveries will be made regarding the physiological functions of mast cell-derived histamine. This chapter outlines the mechanisms of histamine synthesis and release through degranulation and introduces the functions of mast cell-derived histamine in regulating inflammation, itching, immune responses, and energy metabolism.