Hematopoietic stem cells (HSCs) are one of the most widely utilized stem cell populations in the clinic today, in large part due to their robust ability to regenerate and replace the entire blood system after myeloablative injuries. Our research focuses on uncovering the molecular mechanisms underlying how HSCs respond to these injuries. Specifically, we are interested in identifying the key components for directing HSC fate decisions during regeneration. Our studies combine the advantages of zebrafish and murine models to explore the development and genetic regulation of HSC stress response. Zebrafish offer powerful genetic pliability, easily accessible in vivo imaging, numerous transplantation assays, and screening capabilities. Mouse models provide the most robust HSC transplantation assays and the capacity to isolate highly homogeneous HSC populations. Through these studies, we anticipate identifying factors that are critical in the HSC regenerative response, which can be used to inform therapeutic strategies to improve hematopoietic outcomes following myeloablative treatments as well as HSC derivation from pluripotent stem cells.