Mast cells generate and release histamine during anaphylactic reactions, and there is pharmacological evidence that histamine regulates this process via specific receptors. Therefore, we examined human leukemic (HMC-1) and normal skin mast cells for the expression of all four currently known histamine receptors. Both cell types expressed H2 and H4 receptors at mRNA and protein levels, whereas H3 receptor specific mRNA and receptor protein was undetectable. Similarly, immunohistochemistry of cutaneous tissue showed an absence of H3 receptor in these cells. Despite transcription of mRNA, H1 receptor protein was only moderately expressed in HMC-1 cells and was virtually absent in skin mast cells. Furthermore, only H1, H2, and H4 receptors were detectable by Western blot analysis of HMC-1 cells. Radiolabeled histamine binding was strongly inhibited only by H2 (ranitidine)- and H3/H4 (FUB 108)-specific antagonists. Histamine-induced increase of cAMP was inhibited by the H2 receptor antagonist famotidine, whereas induction of IP3 was not observed, making signaling via the H1 receptor unlikely. These data show that human mast cells constitutively express primarily H2 and H4 receptors and that H2 receptors are functionally linked to cellular processes. They provide new insights into the mechanisms that govern auto- and paracrine histamine-induced mast cell functions.