Major depressive disorder (MOD) is a disease often underdiagnosed in adolescents. For adolescents in particular, MOD can have far-reaching implications on developmental, social and emotional functioning. Unfortunately, few guidelines detail consistent means by which to evaluate and treat these patients; significantly more information exists that solely pertains to the adult population. Governing bodies such as the American Academy of Child and Adolescent Psychiatry (AACAP) and Resource for Advancing Children's Health (REACH) recommend that primary care physicians be diligent in their psychiatric analyses and follow-ups with young patients who may be experiencing MOD. Both psychotherapy and medications, either as monotherapy or in combination, should be considered when treating MOD. Selective serotonin reuptake inhibitors (SSRis), particularly fluoxetine, are considered the anti-depressants of choice despite their black box warning pertaining to increased suicidality in children and adolescents. In all cases, benefits of therapy should always be assessed alongside potential risks. Pharmacists can play a significant role in counseling patients on these potential risks and benefits for both the pharmacological and nonpharmacologic aspects of MOD treatment.