The recently identified histamine H₄ receptor has revealed a potential new complexity for the role of histamine in the immune system. To begin to understand the role of this receptor in humans, one must first determine whether homologs exist and can be studied in lower species. To address this, we cloned the rat, mouse, and guinea pig cDNAs corresponding to the recently identified human histamine H₄ receptor. The rat, mouse, and guinea pig H₄sequences are significantly different from the human H₄sequence at 69, 68, and 65% homology, respectively. The tissue distribution of the rat, mouse, and guinea pig H₄ receptors is similar to human in that bone marrow and spleen are the most abundant sources of expression. The human and guinea pig H₄receptors display the highest binding affinity for [³H]histamine (K_D = 5 nM each), whereas the affinities for rat and mouse receptors are substantially lower at 136 and 42 nM, respectively. With respect to the pharmacological profile of known H₃/H₄ ligands, even greater differences in binding affinities exist among the species homologs. There are also substantial differences in the signal transduction response to each of the four species of H₄receptor. This work demonstrates the existence of histamine H₄ receptors in lower species and demonstrates that a clear knowledge of each species pharmacological profile will be essential to elucidate the role of this receptor subtype in vivo.