Hematopoietic Stem Cells (HSCs) are the continuous source of blood and immune cells. HSCs do regenerate along healthy life, and even more so following immunological stimuli. We can prospectively isolate naïve-HSCs; however, there is little understanding of the immune-activated HSCs. Part of the difficulties come from usage of multiple surface-markers, some of which are severely changing after immune stimuli. Using the Fgd5-mCherry reporter mouse allow for better identification of HSCs. Importantly, the primitive HSCs (lineage-cKit+ Sca1+CD150+Fgd5mCherry+) within the bone-marrow do not change by numbers or frequencies following immune-stimulation by pIpC or LPS. Furthermore, we found that these Fgd5+ HSCs retained robust long-term multipotent activity, while the adjacent LSKCD150+Fgd5mCherry- do not. RNA-Seq analysis revealed differently expressed surface markers, including CD317 and CD69. CD317 reveal that all HSCs are rapidly responding to stimuli, while CD69 suggest differences of further activation. Furthermore, chronic long-term immune stimulation exerts deleterious effects on HSCs, and may predispose toward malignancy. Thus, we are highly interested in understanding molecular changes in HSCs after chronic stress. We are also interested in various types of immune stimuli that broaden understanding of HSCs as part of the immune system, our recent findings suggest that HSCs can gain different activation(s), or remain quiescent, according to the type of stimulation. We found improved identification of immune-stimulated HSCs, novel HSC-activation markers, and we are interested in the possible deleterious effect of prolonged stimulation.