This chapter summarizes the information about the transcriptional regulation of histidine decarboxylase (HDC), which is the catabolic enzyme of histamine synthesis, and the activity of histamine in vivo as clarified using HDC gene deficient mice (HDC-KO). The research of the regulatory mechanism of histamine synthesis has been focused on transcriptional and posttranslational aspects. The generation of HDC-KO mice clarified several new pathophysiological functions of histamine. It is now recognized that the activity of histamine is not limited to allergic, peptic and neurological functions as in the old paradigm, but extends to other fields such as cardiology, immunology and infectious diseases. Therefore, this chapter will focus on these newly revealed functions of histamine. For example, histamine was known to be involved in the effector phase of allergic responses, but a role has now been shown in the sensitization phases and in innate immunity. In the allergic bronchial asthma model using HDC-KO mice it was found that histamine positively controls eosinophilia, but not bronchial hypersensitivity. The effect on eosinophils was afterwards shown to be mediated through the activity of the histamine H 4 receptor. The recent advances in the understanding of histamine synthesis and the activity of HDC have dramatically expanded our understanding of the scope of histamine function.