Histamine was the first mediator implicated in mechanisms of allergy, asthma, and anaphylactic shock because it has been discovered to mimic several features of these diseases. In addition to its well-characterized effects in the acute inflammatory and allergic responses, it was recently demonstrated that histamine regulates several essential events in the immune response. Histamine affects the maturation of immune system cells and alters their activation, polarization, chemotaxis, and effector functions. Histamine also regulates antigen-specific T(H)1 and T(H)2 cells, as well as related antibody isotype responses. Histamine binds to 4 different G protein-coupled receptors that transduce signals to cells through distinct pathways. The expression of these receptors on different cells and cell subsets is regulated, and apparently, the diverse effects of histamine on immune regulation are due to differential expression of 4 histamine receptors and their distinct intracellular signals. This article highlights novel discoveries in histamine immunobiology and discusses clinical findings or disease models that indicate immune regulation by histamine.