Hematopoieic stem cells (HSCs) are characterized by their ability to self-renew and differentiate into cells of all hematopoietic lineages. During steady-state, HSCs are mostly quiescent and responsible for normal hematopoietic differentiation. In cases of stress such as infection or injury, HSCs need to be activated and repair the hematopoeitic system in a regenerative response that involves synchronous and hierarchical replacement of the hematopoietic lineages. Multiple signaling pathways constantly specify a complex network of stimuli that HSCs need to decode and act on. Rapid recovery after injury is crucial for patients receiving myeloablative treatments, or suffering from a hematologic malignancy. It is therefore important to understand how signaling pathways control HSC responses during normal hematopoietic differentiation and stress induced regeneration. Our goal is to use zebrafish genetics and genome-wide techniques to understand how signaling pathways synergize and integrate with the internal hematopoietic program and control normal hematopoietic differentiation and stress-induced regeneration. Ultimately our approach may reveal new players of hematopoietic regeneration that can be exploited therapeutically.