OBJECTIVE The hematopoietic stem cell (HSC) compartment is the cornerstone of a lifelong blood cell production but also contributes to the ability of the hematopoietic system to dynamically respond to environmental challenges. This review summarizes our knowledge about the interaction between HSCs and its inflammatory environment during life and questions how its disruption could affect the health of the hematopoietic system. RESULTS The latest research demonstrates the direct role of inflammatory signals in promoting the emergence of the HSCs during development and in setting their steady-state activity in adults. They indicate that inflammatory patho-physiological conditions or immunological history could shape the structure and biology of the HSC compartment, therefore altering its overall fitness. CONCLUSIONS Through instructive and/or selective mechanisms, the inflammatory environment seems to provide a key homeostatic signal for HSCs. Although the mechanistic basis of this complex interplay remains to be fully understood, its dysregulation has broad consequences on HSC physiology and the development of hematological diseases. As such, developing experimental models that fully recapitulate a normal basal inflammatory state could be essential to fully assess HSC biology in native conditions.