The management of pregnant and postpartum women with major depression may be complicated, especially when pharmacological therapies are involved. The most common situations that the clinician encounters in the management of reproductive age women with treatment-resistant depression include: inadvertent conception during treatment; prepregnancy consultation; exacerbation of psychiatric symptoms during pregnancy and/or the postpartum period; and/or prophylactic treatment planning for women at high risk for a postpartum mental illness. This chapter emphasizes the components of an individualized comprehensive risk-benefit assessment, and proposes general algorithms for systematically approaching these situations. It presents a brief overview of the most salient information on the antidepressants, mood stabilizers, benzodiazepines, and electroconvulsive therapy (ECT). Pharmacological augmentation strategies have not been well documented in pregnancy. Considering the variety of augmentation strategies available and lack of information for use in pregnancy, any recommendations are speculative and empirically derived.