The Shraga Segal department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev. Hematopoietic Stem Cells (HSCs) are the continuous source for all types of blood and immune cells. HSCs are mostly quiescent on healthy adult life, but they activate following immunological stimuli. We can prospectively isolate naïve-HSCs; however, there is relatively little understanding of immune-activated HSCs. Part of the difficulties come from usage of multiple surface-markers, some of which are changing drastically after stimuli. We found the Fgd5-mCherry reporter mouse to allow better identification of HSCs. Importantly, we revealed differently expressed surface markers, including CD317 (also known as Bst2) and CD69, being the first HSC-activation markers. Interestingly, various types of immune stimuli cause different activation of HSCs, or even the lack of activation. Furthermore, chronic long-term immune stimulation exerts deleterious effects on HSCs, and may predispose toward malignancy, which is exposed using p53-mutated mice model. In the Myeloid Meeting 2022 we intend to present unpublished data quantifying dosage and timing of HSCs activation following various stimuli. Chronic bacterial infection can cause unexpected prolonged activation of HSCs with, or w/o, severe loss of transplantation potency. Finally, we do focus on the acute-phase of HSC activation, finding surprisingly fast and diverse responses to viral-type or bacterial-stimuli. Taken together, our studies are providing insights into the acute- and chronic-activation of HSCs, with implications to pathogen infection and pre-disposition to malignancies. Understanding the regulation of HSCs will open opportunities to boost essential immune responses, or to prophylactic reduce risk of exhaustion.