Histamine is not only the major mediator of the acute inflammatory and immediate hypersensitivity responses, but has also been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. It can influence numerous functions of the cells involved in the regulation of immune response and hematopoiesis including macrophages, dendritic cells, T lymphocytes, B lymphocytes and endothelial cells. These cells express histamine receptors and also secrete histamine, which can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and effector functions leading to chronic inflammation. Histamine regulates antigen-specific Th1 and Th2 cells, as well as related antibody isotype responses. Histamine acting through its receptor (HR) type 2, positively interferes with the peripheral antigen tolerance induced by T regulatory (T(Reg)) cells in several pathways. The diverse effects of histamine on immune regulation are due to differential expression and regulation of 4 histamine receptors and their distinct intracellular signals. In addition, differences in affinities of these receptors are highly decisive on the biological effects of histamine and agents that target histamine receptors. Although substantial evidence has been accumulated about histamine metabolism, receptors, signal transduction, physiological and pathological effects, the complex interrelationship and cross-talk by histamine, its receptors and other G-protein coupled receptors remain to be understood.