In the adult organisms, millions of cells are replaced every day. The intestinal epithelium is the champion of regeneration among adult tissues. Constant maintenance and regeneration of this complex organ is mediated by intestinal stem cells. However, with age or in pathological conditions, such as inflammatory disease or cancer, intestinal stem cells fail to function properly. Understanding how intestinal stem cells are generated during development is the main focus of our research. We are investigating 1) which embryonic epithelial cells give rise to the adult intestinal stem cells, 2) how embryonic cells in the gut become stem cells, 3) what is the origin of cancer stem cells. To address these questions, we apply tools of mouse genetics, single-cell genomics and ex vivo 3D organoid assays. We have found that adult intestinal stem cells come from molecular heterogeneous embryonic progenitors (Dzama et al., 2017). Currently, we are establishing a functional role for this heterogeneity during epithelial homeostasis and cancer. We have also identified factors that control specification of intestinal stem cells during embryogenesis (Kazakevych et al., 2017; Nigmatullina et al., 2017). We will continue defining signals and cells essential for the specification and maintenance of intestinal stem cells.