Adrenarche is a cell biological and endocrinological puzzle. The differentiation of the zona reticularis in childhood in humans requires special techniques for study because it is confined to humans and possibly a small number of other primates. Despite the rapid progress in the definition of adrenocortical stem/progenitor cells in the mouse, the factors that cause the differentiation of adrenocortical cells into zonal cell types have not been identified. There are, however, many candidates in the Wnt, Hedgehog, and other families of signaling molecules. A suitable system for identifying authentic stem cells, capable of differentiation into all zones, has yet to be developed. It is proposed here that the in vitro differentiation of pluripotent cells, combined with appropriate in vitro and in vivo methods for validating authentic adrenocortical stem cells, is a promising approach to solving these questions.