There is much interest in whether depression and stress may explain the wide variability in the disease course of patients infected with human immunodeficiency virus (HIV). This article summarizes the large body of evidence examining whether depression and stress may have an impact on immune- and disease-related parameters in HIV disease. Furthermore, we review what is known about the underlying biological mechanisms of HIV disease, such as alterations in glucocorticoids and catecholamines, which may help explain these psychoimmune relationships. Our review of the literature finds substantial evidence that chronic depression and stressful events may affect HIV disease progression. We know little, however, regarding the biological mechanisms that may account for these relationships. More research is warranted to investigate how depression and stress might impact HIV disease progression and what types of interventions might mitigate the negative impact of chronic depression and trauma.