The data collected in this work represent the first evidence that G-protein-coupled signalling exist in γδ T cells via histamine and fMLP receptors. The bigenic amine histamine and the bacterial peptide fMLP have been demonstrated to be novel chemoattractant factors for circulating human γδ T cells, which are critical members of the immunological tumor surveillance machinery. Here, we analyzed the influence of histamine on the interaction of human γδ T cells with tumor cells such as the A2058 human melanoma cell line, the human Burkitt's non-Hodgkins lymphoma cell line Raji, the T-lymphoblastic lymphoma cell line Jurkat, and the NK cell-sensitive erythroleukaemia line K562. We found that histamine inhibits the spontaneous cytolytic activity of γδ T cells in response to these cell lines. The downregulation of γδ T cell mediated cytotoxicity involves the histamine receptor subtype 2 (H2R), the activation of Gs proteins and increased cAMP intracellular levels. On the other hand, histamine activates the common signalling pathways of chemotaxins such as Gi-protein-dependent actin reorganization, the increase of intracellular Ca2+ and the induction of migratory response in γδ T lymphocytes. Our data indicate that histamine contributes to the mechanism by which tumor cells escape immunological surveillance. The bacterial-cell-wall-derived peptide N-formyl-Met-Leu-Phe (fMLP) is a well characterized chemotactic factor for phagocytes such as neutrophils, monocytes and dendritic cells. Here, we analyzed the influence of fMLP on isolated human peripheral blood γδ T cells. We found that fMLP induces intracellular calcium transients, actin reorganization, CD11b upregulation and the migration of γδ T cells. Pretreating γδ T cells with pertussis toxin inhibited all fMLP-stimulated cell responses, implicating the involvement of Gi proteins in the induced signalling cascade. The present data suggest that, in addition to phagocytes, N-formyl peptides also regulate the trafficking and activation of γδ T cells.