Since its discovery at the beginning of the 20th century, histamine has been established to play a pathophysiological regulatory role in cellular events through binding to four types of G‐protein‐coupled histamine receptors that are differentially expressed in various cell types. The discovery, at the turn of the millennium, that the histamine H₄ receptor is largely expressed in haemopoietic cells as well as its chemotactic properties designate its regulatory role in the immune system. H₄ receptors modulate eosinophil migration and selective recruitment of mast cells leading to amplification of histamine‐mediated immune responses and eventually to chronic inflammation. H₄ receptor involvement in dendritic cell activation and T cell differentiation documents its immunomodulatory function. The characterization of the H₄ as the immune system histamine receptor directed growing attention towards its therapeutic exploitation in inflammatory disorders, such as allergy, asthma, chronic pruritus and autoimmune diseases. The efficacy of a number of H₄ receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples. However, before reaching decisive conclusions on H₄ receptor pathophysiological functions and therapeutic exploitation, identification of genetic polymorphisms and interspecies differences in its relative actions and pharmacological profile need to be addressed and taken into consideration. Despite certain variations in the reported findings, the available data strongly point to the H₄ receptor as a novel target for the pharmacological modulation of histamine‐transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders.