This descriptive exploratory study explored illness appraisal and spiritual coping of three groups of individuals with life-threatening illness. These were hospice clients with cancer (Ca; n = 10), clients with first myocardial infarction (MI; n = 6), and parents of children with cystic fibrosis (CF; n = 16). Qualitative data were collected by audiotaped face-to-face interviews (parents) and focus groups (MI and Ca). Similarities in illness appraisal and spiritual coping were found across the three groups except appreciation of crafts, which was found only in clients with Ca and causal meaning of parents (CF). Overall, illness was appraised negatively and positively, whereas spiritual coping incorporated existential and religious coping. These findings confirm the psychological theory (Lazarus & Folkman, 1984) and theological theory (Otto, 1950), which guided this study. Recommendations were proposed to integrate spirituality and religiosity in the curricula, clinical practice and to conduct cross-cultural comparative longitudinal research.