There is a high incidence of life event stress, depression, and associated symptoms in individuals with HIV infection/AIDS. Psychological and psychiatric symptomatology in individuals with HIV and AIDS may be related to the progression of AIDS disease. The association between depression, anxiety, and stress with HIV disease progression suggests that neurobiologic and neurophysiologic factors have an important role in modulating HIV. The immune effects caused by changes in behavioral state or brain activity are affected, at least in part, through the neuroendocrine-immune pathways. Life stress and depression may be associated with altered blood levels of CNS-released neuropeptides, including substance P (SP). SP is a powerful immunomodulator which is a critical link between the nervous and immune system. We have investigated the role of the neuropeptide SP and its preferred receptor, neurokinin-1, in HIV infection and AIDS. There are compelling data from our laboratories, as well as the findings in the literature, which demonstrate that SP may play an important role in the pathophysiology of neuropsychiatric disorders, including stress and depression in HIV-infected individuals and in the immunopathogenesis of HIV disease. Modulation of SP activity and SP receptor may offer a novel approach to the treatment of psychiatric disorders and to the design of new anti-HIV therapy.