Blood glucose regulation has likely evolved during early vertebrate evolution to allow and secure the concurrent evolution of complex brains and nervous systems: an inner milieu of constant blood glucose levels through millions of years has provided an extra degree of freedom for the brain to evolve without having to think of getting energy supply. Key regulators of blood glucose, insulin, and glucagon are produced by the dominating cell types of the pancreatic islet of Langerhans: the insulin producing beta cells and the glucagon producing alpha cells. Interestingly, it appears that the beta cell pioneered the formation or the foundation of the pancreatic organ according to current phylogenetic insights. Such phylogenetic aspects of a pancreatic stem cell are at the end discussed in relation to directed differentiation of embryonic stem cells/ES cells towards therapeutic beta cells.