The extant jawless fishes (Agnatha) include the hagfishes and lampreys whose ancestry can be traced through a conserved evolution to the earliest of vertebrates. This review traces the study of the enteropancreatic (EP), endocrine cells and their products in hagfishes and lampreys over the past two centuries. Erika Plisetskaya is one of several prominent comparative endocrinologists who studied the development, distribution or function of the agnathan EP system. Her physiological studies in Russia laid the foundation for her subsequent isolation in North America of the first lamprey EP peptides (insulin and somatostatin) and providing the first homologous radioimmunoassay for agnathan (lamprey) insulin. This review also emphasizes the nature and the method of development of the agnathan endocrine pancreas (islet organ), for it reflects the earliest vertebrate endocrine pancreas originating from intestinal and/or bile-duct epithelia. The lamprey life cycle includes a protracted larval period and a metamorphosis when the adult EP system develops. Differences in morphogenesis during metamorphosis of southern- and northern-hemisphere lampreys dictate that a single cranial mass (islet organ) appear in the former and both a cranial and a caudal principal islet comprises most of the islet organ in holarctic species. There are differences in distribution of cell types and in the primary structure of the peptides in the definitive islet organ of hagfishes and lampreys. The primary structures of insulin, somatostatins, glucagons, glucagon-like peptide, and peptide tyrosine tyrosine are now available for three lamprey species representing three genera and two of the three families. Differences in structure of peptides within, and between, families is providing support for earlier views on the time of divergence of the families and the different genera. It is concluded that due to the ancient lineage and successful habitation of lampreys and hagfishes, and the importance of the EP system to their survival, that their EP systems should be a research focus well into the next century.