We have previously reported that histamine at micromolar concentrations reduces the proliferation of melanoma cell lines. It is also known that melanoma cells express histamine H 1 , H 2 , and H 3 receptors. The aim of this study was to investigate the presence of histamine H 4 receptor (H 4 R) in human melanoma cells and its associated biological processes. To better understand the importance of histamine in tumor development, we explored the expression of H 4 R in human melanoma tissue biopsies. The expression of H 4 R in WM35 and M1/15 cells was analyzed by reverse-transcription-PCR, western blot, and immunocytochemistry. To characterize the biological responses we evaluated cell proliferation by clonogenic assay and 5-bromo-2 0 -deoxyuridine incorporation. In addition, cell senescence and differentiation were determined by b-galactosidase enzyme assay and dopa oxidase activity, respectively. The expression levels of H 4 R were determined by immunohistochemistry in 19 samples of human malignant lesions. Results indicate that melanoma cells express H 4 R at the messenger RNA and protein levels. By using histamine agonists, antagonists, and H 4 R small-interfering RNA we showed that the inhibitory effect of histamine on proliferation was in part mediated through the stimulation of the H 4 R. The decrease in proliferation was associated with an induction of cell senescence and an increase in melanogenesis, which is a differentiation marker of these cells. Furthermore, H 4 R was expressed in 42% of human melanoma biopsies. To our knowledge, this is the first report that describes the presence of the H 4 R in melanoma cells and tissue, suggesting a potential therapeutic application of H 4 R ligands.