The balance between survival and death in many cell types is regulated by small changes in the intracellular content of bioactive sphingolipids. Enzymes that either produce or degrade these sphingolipids control this equilibrium. The findings here described indicate that the lysosomal galactocerebrosidase (GALC) enzyme, defective in globoid cell leukodystrophy, is involved in the maintenance of a functional hematopoietic stem/progenitor cell (HSPC) niche by contributing to the control of the intracellular content of key sphingolipids. Indeed, we show that both insufficient and supraphysiologic GALC activity-by inherited genetic deficiency or forced gene expression in patients' cells and in the disease model-induce alterations of the intracellular content of the bioactive GALC downstream products ceramide and sphingosine, and thus affect HSPC survival and function and the functionality of the stem cell niche. Therefore, GALC and, possibly, other enzymes for the maintenance of niche functionality and health tightly control the concentration of these sphingolipids within HSPCs.