Histamine is a biogenic amine found in a wide variety of invertebrates. Histamine is particularly well studied in arthropods and gastropods where it is involved in local immune responses as well as regulating physiological functions in the gut. Histamine also functions as a neurotransmitter, especially for sensory systems. Previous physiology work of our lab found that histamine activates the sensory system of Crassostraea virginica, eliciting a motor response in the gill. Our earlier cell biology and immunofluorescence work also showed the presence of histamine receptors in ganglia and mantle of C. virginica. Recently the genome of C. virginica and other bivalves have begun to be mapped. We hypothesize that C. virginica contains genes for histamine receptors and that these receptors are similar to those found in other animals, including mammals and humans. To study this we did BLAST searched of the NCBI (National Center for Biotechnology Information) database using DNA and protein sequences of C. virginica histamine 1, 2 and 3 receptor (H1R, H2R, H3R) genes. We found gene matches for the histamine receptors. H1R genes were found on chromosome 8; H2R on chromosomes 1, 2, 5 and 10; and H3R on chromosome 3. Receptor BLASTS of other invertebrates and mammals found matches with very low Expect Values (E Values) and moderately high Percent Identity, signifying similarities of H1R, H2R and H3R of C. virginica to those of other bivalves, gastropods, insects, mice, rats and humans. For H1R, various bivalves had Percent Identity above 60%, but poor matches for gastropods and insects. For H2R, C. gigas had a high match of 82%, but other invertebrates, mice, rats and humans had very low matches. For H3R, C. gigas had a high match of about 75%, while some other bivalves, mice, rats and humans had Percent Identity of about 40%. Gastropods and insects did not show as good matches as other bivalves and various other invertebrates. This study complements our earlier physiology and cell biology studies demonstrating the presence and function for histamine in C. virginica, and shows that the genome of C. virginica contains genes to produce histamine receptors that are similar to those found in other animals. This new information is valuable as it shows that the simple nervous system of histamine can be used to expand studies on histamine neurotransmission.