Perinatal depression mediates a profound impact on maternal and offspring health. Alterations in endocrine and immune function in depressed mothers have been linked to altered stress responses in offspring and less optimal neurodevelopmental outcomes. This chapter reviews the important changes in immune function that have been documented in depressed mothers and seeks to link changes in immune regulatory and endocrine processes to ultimate outcome in offspring. We identify key interactions between the immune system, the Hypothalamic-Pituitary-Adrenal axis and the oxytocin system that are relevant to understanding the dysregulated immune responses in depressed mothers. Additionally, we review how the above changes have been linked to an increased risk of aberrant development of offspring of depressed mothers, as well as the future manifestation of mental illness. Molecular mechanisms relevant to these processes are highlighted. Our work reinforces the potential importance of biomarkers that could be linked to both immune dysfunction and negative developmental outcomes in offspring in perinatal depression. Through improved screening and intervention protocols that incorporate the above approach, significant progress could be made in reducing the large morbidity associated with perinatal depression.