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Postpartum depression (PPD) is a potentially debilitating disorder that develops in a significant percentage of women during the first year after giving birth. Women afflicted with PPD experience long-term consequences, including sadness, guilt, and despair. Offspring may be affected as well. Several investigators have tested psychosocial risk factors for the development of PPD; however, substantial amounts of variance in PPD have gone unexplained with regression on psychosocial variables alone. Likewise, interventions for PPD that have focused on psychosocial risk factors alone have been largely unsuccessful. The unexplained variance and disappointing treatment success could well be due to investigators' failure to address relevant biological changes occurring during the postpartum period. Two biological systems that are affected significantly and remain in flux during the postpartum period are the innate immune system and the hypothalamic-pituitary-adrenal (HPA) axis. Bidirectional interactions between these two systems are well established, and it is generally acknowledged that dysfunction in either system can lead to depression in nonpregnant, nonpostpartum populations. To date, little research has pursued the contribution of these interacting systems to the development of PPD. The purpose of this paper is to review the psychoneuroimmunology of PPD. The central hypothesis presented is that dysregulation in either system individually or in their bidirectional interaction is associated with the development of PPD.