Histamine N -methyltransferase (HNMT; EC 2.1.1.8) was discovered a little over 25 yr ago. Since that time, HNMT has been the subject of numerous investigations, and although these studies have provided a fundamental understanding of this enzyme, HNMT has not been the subject of a comprehensive review or analysis. This is surprising since HNMT and diamine oxidase (DAO; EC 1.3.4.6) are the only known enzymes that terminate the physiologic activity of histamine (HA) in mammals. However, to a large extent the physiologic significance of HNMT remains a conundrum, and the importance of this enzyme may have been overshadowed by the lack of pharmacologic or pathologic conditions that are characterized by abnormalities in HNMT activity.