The cells involved in the regulation of immune responses and hematopoiesis express histamine receptors and secrete histamine. Histamine acting through four types of its receptors has been shown not only to affect chronic inflammatory responses but also to regulate several essential events in the immune response. Histamine signals have a role in the mechanisms of tolerance induced during allergen-specific immunotherapy (SIT), acting mainly through its receptor (HR) type 2. It positively interferes with the peripheral antigen tolerance induced by T regulatory cells in several pathways. The rationale for the concomitant use of H1 antihistamines during SIT is diverse and includes reduction of its immediate side effects as well as enhancement of mechanisms of specific tolerance and anti-inflammatory effects of vaccination.