At steady state, HSCs maintain a balance of self-renewal and differentiation into mature blood cells. However, during external and internal stressors that increase IFNα or IFNγ signaling e.g. infection, aging, and autoimmunity, homeostasis is lost. With excessive IFN signaling, HSCs lose their self-renewal capability and differentiate. Modulating IFN signaling by treating patients with recombinant IFNs or blocking IFN signaling pathways have proven to be effective treatment strategies.