Informal caregivers experience a great deal of stress due to care-related duties and responsibilities. Caregiving stress has the ability to impact caregivers' physical health but has been largely understudied in caregivers of children with a chronic illness. In this study, we examine the associations of stress to both caregiver self-rated health and biomarkers of the hypothalamic-pituitary-adrenal (HPA) axis and immune systems (arginine vasopressin, c-reactive protein, tumor necrosis factor alpha). We also examine whether coping style (proactive, avoidant, support coping) buffers the links of stress to health across 2 different stressor contexts: caregiving for a child with a rare or undiagnosed disease (n = 101) and caregiving for a typically developing child (n = 69). Results indicated perceived stress was linked to worse self-rated health; however, stress was only linked to biological markers of health for caregivers of typically developing children. Results also suggest that coping style may moderate some of the links of stress to health, as proactive coping was linked to lower arginine vasopressin. However, models also suggested the role of coping style may differ based on caregiving context, as support coping was linked to better health only for caregivers of typically developing children, and more proactive coping overall was observed in the rare disease context. Future research should continue to examine how stress and coping interact within different caregiving contexts to protect caregiver health and well-being. What is the significance of this article for the general public?In this study, perceived stress and avoidant coping were linked to worse self-rated health for caregivers of both typically developing children and children with rare diseases, while proactive coping buffered the links of stress to physiological biomarkers. However, some aspects of traditional stress and coping frameworks may not apply under unique stress contexts such as rare disease caregiving, as results indicated stress was only linked to physiological biomarkers of health for caregivers of typically developing children, and these caregivers were the only ones to benefit from social support coping.