Perinatal depression is the most common psychiatric complication of pregnancy, with its detrimental effects on maternal and infant health commonly underrated. There is a pressing need for specific molecular biomarkers, with pregnancy-related decline in brain-derived neurotrophic factor (BDNF) in the blood and downregulation of TrkB receptor in the brain reported in both clinical and preclinical studies. In this review, we highlight the emerging role of BDNF in reproductive biology and discuss evidence suggesting its deficiency as a risk factor for perinatal depression. With the increasing evidence for restoration of serum BDNF levels by antidepressant therapy, the strengthening association of perinatal depression with deficiency of BDNF advocates its potential as a surrogate endpoint for preclinical and clinical studies.