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Postpartum depression (PPD), a biological complication of childbirth, is the most common and the most underdiagnosed postpartum complication, affecting 1 in 7 women. Numerous neuroendocrine mechanisms in the peripartum period, a time of abrupt and dramatic changes in hormone levels, have been identified and correlated with PPD. The withdrawal of reproductive hormones increases depression scores in women with a prior PPD history. Levels of GABA and neurosteroids are altered, whereas increased allopregnanolone levels have been shown to decrease the risk of PPD. This activity reviews the latest insights into the neurobiology of PPD and elucidates the mechanisms of action of the therapies in development as well as of currently approved therapy.