Since Sir Henry Dale, a Nobel laureate in Physiology or Medicine, discovered the activities of histamine in 1910, a large number of studies have been conducted on histamine’s physiological and pathological actions. While histamine was considered an allergy-causing “bad guy,” recent studies have indicated that histamine also has beneficial physiological activities. The guideline for allergic diseases, such as pollenosis and atopic dermatitis, recommends nonsedating antihistamines with low central nervous system (CNS) penetration to avoid suppressing histamine’s CNS actions. Positron emission tomography (PET) is often used to evaluate the efficacy of CNS drugs by determining the drugs’ neuronal receptor occupancy rate. While the blood concentration levels of a drug are frequently determined clinically, i.e., via therapeutic drug monitoring (TDM), CNS drugs do not necessarily show a correlation between their blood concentration levels and effect. Previously, we have reported on brain H1 receptor occupancy measurements of antihistamines, antidepressants, and antipsychotics. In the present review, the results of our previous studies on the significance of brain histamine H1 receptor occupancy of histamine H1 blockers are summarized from the perspective of histamine function in the CNS.