In addition to its well-characterized effects in the acute inflammatory and allergic responses, histamine has been shown to affect chronic inflammation and regulate several essential events in the immune response. Histamine can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and effector functions leading to chronic inflammation. On the other hand histamine acting through its receptor (HR) type 2 positively interferes with the peripheral antigen tolerance induced by T regulatory (Treg) cells in several pathways. Histamine also regulates antigen-specific TH1 and TH2 cells, as well as related antibody isotype responses. These findings provide suitable explanation for the observations in the experimental model of asthma showing that allergic inflammatory responses and bronchial hyperresponsiveness may be susceptible to HR1 blockade. Apparently, the various 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 is highly decisive on the biological effects of histamine and drugs that target histamine receptors. This article highlights novel discoveries in histamine immunobiology and discusses their relevance to the allergic inflammatory responses.