Fatigue is a debilitating symptom of chronic illness that is deleteriously affected by perceived stress, a process particularly relevant to inflammatory disease. Hopefulness, a goal-based motivational construct, may beneficially influence stress and fatigue, yet little research has examined these associations. We assessed the relation between hope and fatigue, and the mediating effect of stress, in individuals with fibromyalgia, arthritis, and inflammatory bowel disease. Covarying age, sex, and pain, stress partially mediated the association between hope and fatigue; those with greater hope reported less stress and consequent fatigue. Therapeutically, bolstering hope may allow proactive management of stressors, resulting in less fatigue.