ATF4 plays a pleiotropic role in the maintenance, function, and differentiation of HSCs. Loss of ATF4 impairs HSC function and hematopoiesis in mouse fetal liver and bone marrow through transcriptional regulation of cytokines in the microenvironment or cell-intrinsic programs. ATF4-deficient bone marrow HSCs display skewed myeloid lineage differentiation and impaired erythropoiesis. In erythroid progenitor cells, ATF4-mediated transcriptional activation of RPS19BP1 is required for ribosome biogenesis and protein synthesis to promote erythropoiesis. Created with BioRender.com.