One in 7 women experience depression during the prenatal and/or postpartum period. Nonpharmacologic approaches are known to be as effective as pharmacologic therapies for mild to moderate depression. However, for women who suffer from moderate to severe depression, antidepressant therapy may be the best option, in combination with nonpharmacologic approaches. Considering the substantial negative impact of untreated perinatal depression, providers of prenatal care need to be prepared to diagnose depression, prescribe first-line antidepressants, and refer to other professionals. The purpose of this article is to assist providers to select the safest, most effective selective serotonin reuptake inhibitor (SSRI) as the first-line antidepressant during pregnancy and lactation. Information about side effects, adverse effects, contraindications, and clinical considerations associated with the use of SSRIs is provided. A brief discussion of nonpharmacologic therapies is provided but is not the focus of this article.