Long-term hematopoietic stem cells (LT-HSCs) replenish the innate and adaptive immune compartments throughout life. Although significant progress has defined the major transcription factors that regulate lineage specification, the architectural proteins that globally coordinate DNA methylation, histone modification, and changes in gene expression are poorly defined. Provocative new studies establish the chromatin organizer special AT-rich binding protein 1 (Satb1) as one such global regulator in LT-HSCs. Satb1 is a nuclear organizer that partitions chromatin through the formation of cage-like structures. By integrating epigenetic and transcriptional pathways, Satb1 coordinates LT-HSC division, self-renewal, and lymphoid potential. Unexpected among the assortment of genes under Satb1 control in hematopoietic stem cells (HSCs) are cytokines, a finding that takes on additional importance with the provocative finding that short-term HSCs and downstream multipotent progenitors are potent and biologically relevant cytokine secretors during stress-mediated hematopoiesis. Together, these studies reveal a new mechanism of fate regulation and an unforeseen functional capability of HSCs.