Spiritual issues play a prominent role for patients with cancer. Studies have demonstrated a positive connection between a patient’s spirituality and health outcomes, including quality of life, depression and anxiety, hopefulness, and the ability to cope with illness. Spiritual or existential distress is prominent in patients with cancer. Models are described that identify ways for clinicians to identify or diagnose spiritual or existential distress, and to attend to that distress. It is critical that all clinicians assess for spiritual distress as part of a routine distress assessment, identify appropriate treatment strategies, and work closely with trained spiritual care professionals.