Major depressive disorder (MDD) is a highly prevalent disease often associated with significant medical comorbidity. However, limited data are available examining the associated symptoms of MDD, especially the painful physical symptoms that frequently occur in patients. The presence of these physical symptoms greatly reduces a clinician's ability to recognize and diagnose MDD, ultimately leading to poor treatment outcome. While the treatment goal of MDD is complete remission of all symptoms and the patient's return to full-functioning capacity, if physical symptoms persist, the patient does not achieve functional recovery. Severe consequences have been associated with incomplete remission and residual symptoms, including greater disability and health care costs, plus the increased risk of relapse, morbidity, and mortality. In the treatment of MDD, the noradrenergic, serotonergic, and dopaminergic neural pathways have been found to be affected by depression. More specifically, these neural pathways may correlate with certain psychological and physical symptoms of depression. By studying the effects of antidepressant medications on specific neurotransmitters, antidepressant therapies could be matched to treat specific symptoms of depression. To achieve the goal of remission, clinicians must first determine the best rating method to identify and accurately evaluate the physical symptoms of depression in addition to the core mood symptoms. Therefore, further studies are needed to aid our assessment of physical symptoms and to meet the challenge of effectively matching treatments to a patient's specific symptoms.