Background: The large body of empirical research suggesting that patients’ spiritual and existential experiences influence the disease process has raised the need for health care professionals to understand the complexity of patients’ spiritual pain and distress. Objective: The current study explores the multidimensional nature of spiritual pain, in patients with end-stage cancer, in relation to physical pain, symptom severity, and emotional distress. Design/measurements: The study combines a quantitative evaluation of participants’ intensity of spiritual pain, physical pain, depression, and intensity of illness, with a qualitative focus on the nature of patients’ spiritual pain and the kinds of interventions patients believed would ameliorate their spiritual pain. Setting/subjects: Fifty-seven patients with advanced stage cancer in a palliative care hospital were interviewed by chaplains. Results: Overall, 96% of the patients reported experiencing spiritual pain, but they expressed it in different ways: (1) as an intrapsychic conflict, (2) as interpersonal loss or conflict, or (3) in relation to the divine. Intensity of spiritual pain was correlated with depression (r 0.43, p 0.001), but not physical pain or severity of illness. The intensity of spiritual pain did not vary by age, gender, disease course or religious affiliation. Conclusions: Given both the universality of spiritual pain and the multifaceted nature of pain, we propose that when patients report the experience of pain, more consideration be given to the complexity of the phenomena and that spiritual pain be considered a contributing factor. The authors maintain that spiritual pain left unaddressed both impedes recovery and contributes to the overall suffering of the patient.