Does stress management affect psychological and immune functioning in persons with human immunodeficiency virus infections? Stress-management techniques, such as relaxation training and imagery, cognitive restructuring, coping-skills training, and interpersonal-skills training, may reduce anxiety, depression, and social isolation in HIV-infected persons by lowering physical tension and increasing a sense of control and self-efficacy. A psychoneuroimmunologic model is proposed wherein these psychological changes are hypothesized to be accompanied by an improved ability to regulate neuroendocrine functioning, which in turn may be associated with a partial normalization of immune system functions such as lymphocyte proliferation and cytotoxicity, providing more efficient surveillance of latent viruses that may contribute directly to increased HIV replication and generate opportunistic infections or cancer if left unchecked. Such a normalization of stress-associated immune system decrements are hypothesized to forestall or minimize increases in viral load and expression of clinical symptoms. This model is useful for testing the factors contributing to the health effects of stress-management interventions in HIV-infected persons. In this context, one general research strategy for testing the effects of stress-management interventions is to target them toward the more prevalent psychosocial challenges that HIV-infected people face at various points in the disease process; enroll an HIV-infected population (eg, HIV-positive homosexual and bisexual men) into a randomized trial; and monitor changes in cognitive, affective, behavioral, and social factors in parallel with hormonal, immunologic, viral, and clinical changes over the course of time. This article will review the major psychoneuroimmunologic findings that have emerged using this paradigm and suggest future research directions and clinical applications.