Postpartum respiratory depression is a complex, multifactorial issue that encompasses a patient’s baseline preexisting conditions, certain pregnancy-specific conditions or complications, as well as the iatrogenic element of various medications given in the peripartum period. In this review, we discuss many of these factors including obesity, sleep-disordered breathing, chronic lung disease, neuromuscular disorders, opioids, preeclampsia, peripartum cardiomyopathy, postpartum hemorrhage, amniotic fluid embolism, sepsis, acute respiratory distress syndrome (ARDS), and medications such as analgesics, sedatives, anesthetics, and magnesium. Current recommendations for screening, treatment, and prevention are also discussed.