The hematopoietic stem cell (HSC) system is a paradigm for stem cell studies.HSCs are a population of multipotent cells that can self-renew and differentiate into all blood lineages.HSC development must be tightly controlled which involves a complex of extrinsic signaling and intrinsic factors.Use of the zebrafish model to study the regulation of HSCs in vivo has resulted in a great deal of information concerning HSC biology in vertebrates.I will talk about our recent progress on zebrafish HSC development using functional genomics approaches, with particular focus on how developmental signaling controls hemogenic endothelium-derived HSC specification.These new findings will facilitate a better understanding of HSC programming at molecular level, and may help to design new strategies for the generation of transplantable and functional HSCs in vitro.