In this chapter I focus on the emergence of endoderm, the origin of these cells and their organization in space. I also discuss the molecular events that lead to endoderm formation and how endoderm can be molecularly defined. Although the molecular control of endoderm formation has initially been deciphered using Xenopus, Zebrafish, sea urchin and several other species many molecular switches have been confirmed in mice. This article preferentially cites references in the mouse model system but data from other model organisms are used when they provide important information missing in mice. Extensive references to other species can be found in Grapin-Botton; Constam, 2007 and Stainier, 2002. This article presents endoderm engineering from ES cells and provides molecular triggers and landmarks that may be used for optimized engineering based on normal development. Due to the similarity of markers between definitive and extraembryonic endoderm and the recent discovery that visceral endoderm can contribute to the digestrive tract, the generation of these lineages is also discussed (Kwon et al., 2008). Although endoderm stem cells, that is stem cells endowed with the ability to give rise to all endodermal derivatives but not ectoderm or mesoderm, have not been reported yet, there are stem cells in specific endodermal organs which will be discussed in the following chapters.