Advanced and progressive illnesses bring existential suffering to patients as an inevitable consequence of the disease and its treatment. Physicians need a typology of existential distress to aid its recognition and improved management. The major forms of existential challenge include (1) death anxiety, (2) loss and change, (3) freedom with choice or loss of control, (4) dignity of the self, (5) fundamental aloneness, (6) altered quality of relationships, (7) our search for meaning, and (8) mystery about what seems unknowable. An adaptive response to each challenge promotes equanimity, peace, and fulfillment while sustaining engagement with life, creativity, and joy. Physicians can do much to nurture courage and maintain each person's sense of meaning, value, and purpose.