Interest in the relationship between spirituality, religion, and clinical care has increased in the last 15 years, but clinicians need more concrete guidance about this topic. This article defines spirituality and religion, identifies the fundamental spiritual issues that serious illness raises for patients, and argues that physicians have a moral obligation to address patients' spiritual concerns. Religions often provide patients with specific moral guidance about a variety of medical issues and prescribe rituals that are important to patients. Religious coping can be both positive and negative, and it can impact patient care. This article provides concrete advice about taking a spiritual history, ethical boundaries, whether to pray with patients, and when to refer patients to chaplains or to their own personal clergy.