Histamine, a major neurotransmitter both in vertebrates and invertebrates, transmits its actions through a set of well-known receptors. In vertebrates, these receptors belong to the family of G-protein-coupled receptors. In invertebrates, the few well-characterized actions of histamine are transmitted through ionotropic histamine receptors. To evaluate if metabotropic histamine receptors are part of the invertebrate histaminergic signaling cascade, I identified the complete set of metabotropic bioamine receptors from two invertebrates, whose entire genome has been sequenced: the fruitfly Drosophila melanogaster and the soil nematode Caenorhabditis elegans. A comparison with representatives of all groups of metabotropic bioamine receptors from vertebrates and invertebrates showed that none of these receptors clusters together with any of the four groups of vertebrate histamine receptors. This implies that no direct homologues to vertebrate metabotropic histamine receptor are present in invertebrates. Therefore, it is reasonable to account that the histaminergic neurotransmission in invertebrates is exclusively transmitted through ionotropic histamine receptors and that metabotropic histamine receptors evolved after the split between vertebrates and invertebrates.