Although prior research has examined how early adversity and chronic stress exposure relate to hypothalamic-pituitary-adrenal (HPA) axis responses to acute stress, to date, no studies have examined how stressors occurring over the entire lifespan predict such responses. To address this issue, we recruited 61 healthy young adults and measured their exposure to 55 different types of acute life events and chronic difficulties occurring over the lifespan. In addition, we characterized differences in participants' HPA axis responses to acute stress by measuring their salivary cortisol and DHEA responses to the Trier Social Stress Test for Groups. Greater cumulative stress exposure was associated with a blunted cortisol response, but a heightened DHEA response, to the acute stressor. Moreover, it was participants' exposure to these stressors (i.e., lifetime count), not their perceived severity, which predicted their cortisol and DHEA responses to acute stress. Furthermore, differential effects were observed by stress exposure domain. Notably, only adulthood and marital/partner stressors significantly predicted cortisol responses to acute stress, whereas stress was more uniformly associated with DHEA responses to the acute stressor. These results thus reveal how cumulative stress exposure is associated with HPA axis responsivity to acute stress, while highlighting the fact that different stressors may have substantially different associations with these biological outcomes.