MORE THAN 1.1 MILLION INDIVIDUALS IN THE United States live with human immunodeficiency virus (HIV) infection. Since the mid1990s, much of the clinical, behavioral, and psychosocial research has rightly focused on how to most effectively use combination antiretroviral therapy, improve adherence to medications, and address the shortterm complexities of caring for this population. Success on these fronts has led to improvements in survival and quality of life. Life expectancies for patients newly diagnosed with HIV infection increased from 10.5 to 22.5 years from 1996 to 2005. The reality of patients living with HIV infection for decades will require physicians and the health care system to confront 4 critical issues. First, HIV-infected patients will likely require continuous, life-long therapy. Recent guidelines recommend starting therapy earlier, with a modeling analysis suggesting treatment should be started as soon as possible after diagnosis. Adherence both to medications and to medical care appointments is the sine qua non of long-term survival with HIV infection. Once optimal adherence is achieved, it can only decline, and, in general, adherence in a population diminishes with time. Yet surprisingly little is known about medication adherence and retention in care beyond a 1-year or 2-year horizon. For instance, what are the long-term patterns of adherence and retention in care, and what factors determine a patient’s adherence? How can adherence to appointments and medications over a long period be maximized? Also, what approaches will best reengage patients in care after lapses? The long-term roles of expensive modalities such as directly observed therapy, electronic pill boxes, outreach, and multifaceted interventions need to be defined. Failure to understand how to maximize adherence and retention in care will forfeit many of the gains made in the last decade and a half. Second, aging patients with HIV are more likely to develop the metabolic syndrome consisting of diabetes, hyperlipidemia, and obesity. These patients are at increased risk of cardiovascular disease, liver disease, renal disease, non−AIDS-defining malignancies, altered bone metabolism, pulmonary disease, depression, and neurocognitive impairment. There is little evidence on how to best screen for and manage these long-term metabolic, oncologic, and cardiovascular risks and complications. Little is known about how these physical and mental complications affect patients’ quality of life, long-term medication adherence, and psychosocial well-being. What coping mechanisms do patients with HIV evoke daily over a long period and how can this information be used to help patients living with HIV? What roles do spirituality, stigma, and social relationships play as patients manage their chronic infection and its complications over the years? Do long-term coping and social support mechanisms differ by race/ethnicity, gender identity, sexuality, and socioeconomic status? The emotional, psychological, and physical toll family and friends experience while caring for patients with HIV infection over the long-term is also currently poorly understood. What interventions would maximize and maintain patients’ overall health and quality of life? Third, improved survival has brought about challenges in sexual and reproductive health. How do patients maintain safer sexual relationships over decades and how should this be promoted? In addition, individuals living with HIV infection with such improved prognoses are now more interested in having children. What methods of attaining parenthood achieve a balance of effectiveness, safety, and cost? How should levels of HIV transmission risk be conveyed to potential parents, so they can make an informed decision? Fourth, how best to complete the transformation of programs that provide and fund HIV health care both in the United States and in the developing world must be studied. These programs were initially designed to treat patients with HIV infection for the short term to keep them alive and out of the hospital. These programs have evolved into a complex, multilayered set of services that are minimally integrated but manage to provide excellent care to many patients. However, these programs are not well equipped to provide integrated, comprehensive care to HIV patients over their projected lifespan. A systematic review article found that there still is not a clear under-