Depression is the most frequent psychiatric disorder in multiple sclerosis (MS) patients. The etiology of depression is multifactorial and likely associated with psychosocial stress, focal demyelinating lesions, and immune dysfunction. Proper diagnosis and severity assessment are critical prior to initiation of therapy. Patients with suicidal ideation should be referred for immediate psychiatric consultation and be closely monitored. While more therapeutic trials for depression in MS are needed, MS patients have been shown to respond to current antidepressant medications and psychotherapy. Unfortunately, patients with MS and major depression or suicidal thoughts are often underassessed and therefore not diagnosed. Unlike other aspects of MS, depression is treatable. Early intervention in depression can prevent declines in quality of life and even death from suicide. This article reviews the unique features, assessment, and treatment of depression in MS. MS care providers should vigilantly assess depression and suicide risk in their patients.