Background Providing family care to children who have a chronic physical condition is often a stressful experience, yet a portion of maternal caregivers are able to do so without psychological distress. Specific Aims: On the basis of the multivariate conceptual model proposed by J. L. Wallander, J. W. Varni, L. Babani, C. B. DeHaan, et al. (1989), perceptions of hope and social support were hypothesized to serve as resilience factors against distress in mothers of children with chronic physical conditions. Direct, moderating, and mediating relationships among these variables were tested. Participants: One hundred eleven mothers of 5- to 18-year-old children who had cerebral palsy, spina bifida, or insulin-dependent diabetes mellitus. Main Outcome Measures: Hope Scale, Social Support Questionnaire-6, Brief Symptom Inventory, Parents of Children With Disabilities Inventory. Results: There were no differences in distress among mothers raising children with different conditions. Both hope and social support were associated negatively and uniquely with distress in these mothers. Perceptions of hope moderated the relationship between disability-related stress and maladjustment, suggesting a buffering effect when stress is high. However, hope did not appear to be a mediator of the relationship between social support and distress. Significance: These findings enhance our conceptual understanding of distress in maternal caregivers of children with a chronic physical condition. They also support improving sense of hope as is done in some problem-solving training programs to enhance coping in distressed individuals.