Depression is a common psychiatric comorbidity in Parkinson's disease (PD) and contributes to significant impairments in cognitive, functional, motor, and social performance. This results in reduced quality of life, higher levels of care dependency, and increased caregiver burden. When treating depression, it is important to ensure that the patient's response to treatment will be adequately monitored. This can be accomplished in neurology or primary care settings, or in clinical settings with interdisciplinary treatment teams. Mental health services should be engaged early as a component of ongoing comprehensive care. This article reviews a general approach to treating the pharmacotherapy of depression in PD. Ultimately, clinicians should rely on empiric assessments of known risks and putative benefits to guide treatment decisions and should include a targeted and individualized multimodal approach that utilizes psychotherapeutic interventions along with pharmacologic therapies.