Large-scale gene duplications occurred early in the vertebrate lineage after the split with protochordates. Thus, protochordate hormones and their receptors, transcription factors, and signaling pathways may be the foundation for the endocrine system in vertebrates. A number of hormones have been identified including cionin, a likely ancestor of cholecytokinin (CCK) and gastrin. Both insulin and insulin-like growth hormone (IGF) have been identified in separate cDNAs in a tunicate, whereas only a single insulin-like peptide was found in amphioxus. In tunicates, nine distinct forms of gonadotropin-releasing hormone (GnRH) are shown to induce gamete release, even though a pituitary gland and sex steroids are lacking. In both tunicates and amphioxus, there is evidence of some components of a thyroid system, but the lack of a sequenced genome for amphioxus has slowed progress in the structural identification of its hormones. Immunocytochemistry has been used to tentatively identify a number of hormones in protochordates, but structural and functional studies are needed. For receptors, protochordates have many vertebrate homologs of nuclear receptors, such as the thyroid, retinoic acid, and retinoid X receptors. Also, tunicates have cell surface receptors including the G-protein-coupled type, such as β-adrenergic, putative endocannabinoid, cionin (CCK-like), and two GnRH receptors. Several tyrosine kinase receptors include two epidermal growth factor (EGF) receptors (tunicates) and an insulin/IGF receptor (amphioxus). Interestingly, neither steroid receptors nor a full complement of enzymes for synthesis of sex steroids are encoded in the Ciona genome. Tunicates appear to have some but not all of the necessary molecules to develop a vertebrate-like pituitary or complete thyroid system.