Palliative care of persons with HIV and AIDS has changed over the course of the first three decades of the pandemic. The most radical shifts occurred in the second decade with the introduction of combination antiretroviral therapy and other advances in HIV care. In the United States and throughout the world, progress in prevention of HIV transmission has not kept pace with progress in treatment, thus the population of persons living with AIDS continues to grow. Furthermore, economic, psychiatric, social, and political barriers leave many persons without access to adequate HIV care. As a result, persons who lack access to care may need palliative care for late-stage AIDS while persons with access to AIDS treatments are more likely to need palliative care for multimorbid medical illnesses such as cardiovascular disease, cancer, pulmonary disease, and renal disease. Palliative care of persons with HIV and AIDS cannot be confined to the end of life. We present palliative care on a continuum as part of an effort to alleviate suffering and attend to pain, emotional distress, and existential anxiety during the course of the illness. We will provide guidelines for psychiatric and palliative care and pain management to help persons with AIDS cope better with their illnesses and live their lives to the fullest extent, and minimize pain and suffering for them and their loved ones. This chapter reviews basic concepts and definitions of palliative and spiritual care, as well as the distinct challenges facing clinicians involved in HIV palliative care. Finally, issues such as bereavement, cultural sensitivity, communication, and psychiatric contributions to common physical symptom control are reviewed. The terms palliative care and palliative medicine are often used interchangeably. Modern palliative care has evolved from the hospice movement into a more expansive network of clinical care delivery systems with components of home care and hospital-based services (Butler et al., 1996; Stjernsward and Papallona, 1998). Palliative care must meet the needs of the “whole person,” including the physical, psychological, social, and spiritual aspects of suffering (World Health Organization, 1990).