Human cytomegalovirus (HCMV) is a herpesvirus with a genome of 230 kilobases (Kb) encoding about 200 genes. Although infection is generally innocuous, HCMV causes serious congenital and neonatal disease, and is a dangerous opportunistic pathogen in immune-deficient individuals. We have identified a family of three HCMV genes which encode polypeptides containing seven putative membrane-spanning domains, and a series of well-defined motifs characteristic of the rhodopsin-like G protein-coupled receptors (GCRs). By these criteria all three of the HCMV sequences are homologous to cellular GCRs. Members of this receptor family function in visual signal transduction, regulation of homeostasis, and development, and include known and potential oncogenes. These receptors are activated by photons or small molecules such as neurotransmitters, and glycoprotein hormones. The finding of viral-encoded GCR homologues implies a further level of complexity in the interactions between HCMV and its host, and may provide a potential pathway for virally transformed cell proliferation. Their identification could permit the development of a novel class of antiviral drugs analogous to beta-adrenergic receptor antagonists.