Zebrafish, an ideal animal model for studying human hematopoiesis and hematopoietic diseases, has been widely used to study occurrence and migration of hematopoietic stem cell (HSC), interaction between HSCs and microenvironment, as well as pathogenesis of hematopoietic diseases. Recent studies revealed that the hypoxic stress signaling pathway plays an essential role in in vivo development and in vitro culture and expansion of HSCs. The key factors in this signaling pathway and the mechanisms of regulating downstream target genes are considerably conserved between human and zebrafish. As a complement to mouse models, zebrafish presents some distinct advantages for studies on this area. Utilization of the zebrafish model for studying the role of hypoxic stress in hematopoiesis and hematopoietic diseases should be helpful for further understanding the mechanisms of hematopoiesis and the occurrence of hematopoietic diseases and provide novel ideas for the treatment of hematopoietic diseases.