Abstract: Chronic, sustained exposure to stressors can profoundly impact tissue homeostasis and regeneration. However, how stress leads to tissue changes remain largely elusive. Here, we report that the adrenal gland-derived stress hormone corticosterone (the cortisol equivalent in rodents) enforces hair follicle stem cell quiescence in mice. Without corticosterone, hair follicle stem cells lose quiescence and enter continuous rounds of regeneration cycles throughout life with no signs of exhaustion. Conversely, under chronic stress, elevated corticosterone levels prolong hair follicle stem cell quiescence and inhibit hair follicle regeneration. Mechanistically, corticosterone acts on the dermal niche to suppress the expression of Growth Arrest Specific 6 (Gas6), a secreted factor that stimulates hair follicle stem cell activation. Of significance, restoring Gas6 expression levels is sufficient to overcome the stress-induced regeneration block on hair follicle stem cells. Our findings delineate a cellular and molecular mechanism by which stress leads to defects in tissue regeneration. Moreover, we identify corticosterone as a potent systemic inhibitor of hair follicle stem cell activity via its impact on the niche, and demonstrate that removal of such inhibition drives hair follicle stem cells into continuous regeneration cycles without losing stem cell potential.