Depression pharmacotherapy is the predominant treatment available in the rural United States, yet little is known about the broader contextual factors that rural consumers and providers identify as shaping pharmacotherapy use. Thematic analysis was employed to identify emergent themes from interviews and focus groups about pharmacotherapy adherence, effectiveness, and treatment decisions conducted with Appalachian Kentucky women with depression (N = 37) and diverse healthcare providers who care for this population (N = 21). Pharmacotherapy was seen as inadequate to treat depression in the context of extensive socioeconomic burdens and other health comorbidities. Participants felt that providers over-prescribed pharmacotherapy, a pattern attributed to deficiencies in the rural healthcare system overall. Efforts to improve treatment engagement must acknowledge the significant doubts that rural consumers hold about the potential of pharmacotherapy and should consider the utility of extending broader strategies to address the social conditions shaping vulnerability to depression.