Patients facing serious or life-threatening illness experience challenges to their psychological, social, and spiritual lives as well as to their physical function and comfort. Physicians may be accustomed to focusing on the biomedical aspects of illness, but they have a critical role in assessing the patient's psychosocial issues to identify sources of distress and help implement a plan for mitigating them. An appropriate psychosocial assessment requires a methodical and rigorous approach and includes assessment of any psychosocial issue affected by or affecting a patient's experience of illness. This chapter outlines a structured approach to addressing psychosocial issues by discussing (1) the doctor-patient relationship; (2) coping with illness; (3) family dynamics and caregiving; (4) ethnic and cultural issues; (5) religious, spiritual, and existential issues; (6) mental health issues, including adjustment disorder, depression, anxiety, personality disorders, aberrant drug behaviors, and major mental health issues; and (7) grief and bereavement. Tables outline psychosocial assessment questions, factors predisposing patients with serious illness to depression, risk factors for suicide in patients with terminal illness, and classes of antidepressants, anxiolytics, and sedatives. The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire is provided, as well as a list of Web sites with further resources about psychosocial issues in serious illness. This review contains 1 highly rendered figure, 6 tables, and 216 references.