Perinatal depression (PND) impacts a significant number of women during their reproductive years. Despite the consensus on the serious risk it poses to maternal well-being and infant development, important gaps regarding the understanding of its pathophysiology and management persist. In this chapter, we discuss the evolution of the concept and clinical characterization of PND. We discuss etiological and risk factors for PND, followed by the different pathophysiological mechanisms involved in this condition. Since some of the underlying mechanisms involved in the pathophysiology of PND might be distinct from the ones observed in major depressive disorder, a specific treatment approaches is often necessary for the management of that condition. Other than brexanolone, no medications are FDA-approved for the treatment of PND at present and, apart from pharmacotherapy, patient and family education are crucial for optimal outcomes, emphasizing the importance of a multidisciplinary approach for the management of PND. Other aspects of that disorder, such as transcultural factors, stigma, and the importance of timely screening are also discussed.