The mainstays of treatment for peripartum depression are psychotherapy and antidepressant medications. More research is needed to understand which treatments are safe, preferable, and effective. Postpartum depression, now termed peripartum depression by the DSM-V, is one of the most common complications in the postpartum period and has potentially significant negative consequences for mothers and their families. This article highlights common clinical challenges in the treatment of peripartum depression and reviews the evidence for currently available treatment options. Psychotherapy is the first-line treatment option for women with mild to moderate peripartum depression. Antidepressant medication in combination with therapy is recommended for women with moderate to severe depression. Although pooled case reports and small controlled studies have demonstrated undetectable infant serum levels and no short-term adverse events in infants of mothers breastfeeding while taking sertraline (Zoloft) and paroxetine (Paxil), further research is needed including larger samples and long-term follow-up of infants exposed to antidepressants via breastfeeding controlling for maternal depression. Pharmacologic treatment recommendations for women who are lactating must include discussion with the patient regarding the benefits of breastfeeding, risks of antidepressant use during lactation, and risks of untreated illness. There is a growing evidence base for nonpharmacologic interventions including repetitive transcranial magnetic stimulation, which may offer an attractive option for women who wish to continue to breastfeed and are concerned about their infants being exposed to medication. Among severe cases of peripartum depression with psychosis, referral to a psychiatrist or psychiatric advanced practice registered nurse is warranted. Suicidal or homicidal ideation with a desire, intent, or plan to harm oneself or anyone else, including the infant, is a psychiatric emergency, and an evaluation by a mental health professional should be conducted immediately. Peripartum depression treatment research is limited by small sample sizes and few controlled studies. Much work is still needed to better understand which treatments women prefer and are the most effective in ameliorating the symptoms and disease burden associated with peripartum depression.