The physiologic functions of histamine have been recognized for more than 100 years, yet new roles are still being uncovered. Most importantly, a newly discovered receptor of the amine has helped refine our understanding of histamine. This new receptor, the histamine H4 receptor (H4R), has a higher affinity for histamine compared with the histamine H1 receptor and appears to be more selectively expressed, found mainly on hematopoietic cells. H4R is involved in chemotaxis and inflammatory mediator release by eosinophils, mast cells, monocytes, dendritic cells, and T cells. Studies in animal models using selective antagonists or H4R-deficient mice have shown a role for the receptor in inflammation in vivo. In particular, H4R antagonists have shown promise in experimental models of asthma and pruritus, two conditions where currently marketed antihistamines targeting the histamine H1 receptor are not optimally effective in humans. Thus, a new class of H4R-specific antihistamines may be distinctively effective in treating allergic diseases associated with chronic pruritus and asthma.