We tested a model in which psychosocial and disease-related variables act as multiple protective and risk factors for psychological distress in patients with metastatic cancer. We hypothesized that depression and hopelessness constitute common pathways of distress, which mediate the effects of psychosocial and disease-related factors on the desire for hastened death. This model was tested on a cross-sectional sample of 406 patients with metastatic gastrointestinal or lung cancer recruited at outpatient clinics of a Toronto cancer hospital, using structural equation modeling. The results supported the model. High disease burden, insecure attachment, low self-esteem, and younger age were risk factors for depression. Low spiritual well-being was a risk factor for hopelessness. Depression and hopelessness were found to be mutually reinforcing, but distinct constructs. Both depression and hopelessness independently predicted the desire for hastened death, and mediated the effects of psychosocial and disease-related variables on this outcome. The identified risk factors support a holistic approach to palliative care in patients with metastatic cancer, which attends to physical, psychological, and spiritual factors to prevent and treat distress in patients with advanced disease.