Hematopoiesis is a complex process through which immature bone marrow precursor cells mature into all types of blood cells. Although the association of hematopoietic lineage bias (including anemia and neutrophilia) with chronic inflammatory diseases has long been appreciated, the causes involved are obscure. Recently, cytosolic multiprotein inflammasome complexes were shown to activate inflammatory and immune responses, and directly regulate hematopoiesis in zebrafish models; this was deemed to occur via cleavage and inactivation of the master erythroid transcription factor GATA1. Herein summarized are the zebrafish models that are currently available to study this unappreciated role of inflammasome-mediated regulation of hematopoiesis. Novel putative therapeutic strategies, for the treatment of hematopoietic alterations associated with chronic inflammatory diseases in humans, are also proposed. The activation of the Nlrp1a inflammasome in mouse hematopoietic stem and progenitor cells (HSPCs) triggers their pyroptotic death and prolonged leukopenia upon chemotherapy or viral infection.The NLRP3 inflammasome drives HSPC clonal expansion and pyroptosis in myelodysplastic syndrome patients.Emerging evidence from zebrafish models suggests that the canonical inflammasome autonomously regulates the erythroid–myeloid cell fate decision of HSPCs, and terminal erythroid differentiation through the cleavage of Gata1. This mechanism appears to be evolutionarily conserved since pharmacological inhibition of caspase 1 (Casp1) in mouse hematopoietic stem cells (HSCs) results in a rapid increase in Gata1 protein, leading to erythroid differentiation.Pharmacological inhibition of the canonical inflammasome rescues zebrafish disease models of neutrophilic inflammation, anemia associated with chronic diseases, and Diamond–Blackfan anemia.