The sequencing of the starlet sea anemone (Nematostella vectensis) genome provides opportunities to investigate the function and evolution of genes associated with chemical neurotransmission and hormonal signaling. This is of particular interest because sea anemones are anthozoans, the phylogenetically basal cnidarians least changed from the common ancestors of cnidarians and bilaterian animals, and because cnidarians are considered the most basal metazoans possessing a nervous system. This analysis of the genome has yielded 20 orthologues of enzymes and nicotinic receptors associated with cholinergic function, an even larger number of genes encoding enzymes, receptors and transporters for glutamatergic (28) and GABAergic (34) transmission, and two orthologues of purinergic receptors. Numerous genes encoding enzymes (14), receptors (60) and transporters (5) for aminergic transmission were identified, along with four adenosine-like receptors and one nitric oxide synthase. Diverse neuropeptide and hormone families are also represented, mostly with genes encoding prepropeptides and receptors related to varying closeness to RFamide (17) and tachykinin (14), but also galanin (8), gonadotropin-releasing hormones and vasopressin/oxytocin (5), melanocortins (11), insulin-like peptides (5), glycoprotein hormones (7), and uniquely cnidarian peptide families (44). Surprisingly, no muscarinic acetylcholine receptors were identified and a large number of melatonin-related, but not serotonin, orthologues were found. Phylogenetic tree construction and inspection of multiple sequence alignments reveal how evolutionarily and functionally distant chemical transmitter-related proteins are from those of higher metazoans.