Depressive disorders are commonly comorbid with neurological illness and often underdiagnosed (Fink P, Hansen MS, Sondergaard L, Frydenberg M. J Neurol Neurosurg Psychiatry 74(817):9, 2003; Thielscher C, Thielscher S, Kostev K. Ger Med Sci. 11:Doc02, 2013). Depression in neurology patients is associated with worse quality of life (Luoni C, Bisulli F, Canevini MP, De Sarro G, Fattore C, Galimberti CA et al. Epilcpsin 52(12):2181–2191, 2011; Fernandez-Jimenez E, Arnell P. Mull Seier 2I(11):1468–1472, 2015; Schrag A. J Neurol Sci 248(1–2):151–157, 2006) and increased disability, pain, and somatic symptoms (Carson AJ, Ringhauer B, Mackenzie L, Warlow C, Sharpe M. J Neurol Neurosurg Psychiatry 68:202–206, 2000). Conversely, remission of depression can improve outcomes (Chemerinski E, Robinson RG, Arndt S, Kosier JT. J Nerv Ment Dis 189:421–425, 2001). Depression is also a risk factor for poor treatment adherence (DiMalleo RM, Lepper HS, Croghan TW. Arch Intern Med 160:2101–2107, 2000). This chapter emphasizes the importance of screening for depression across its spectrum including subsyndromal depression and persistent depressive disorder. Treatment strategies for depression are discussed, including antidepressants and psychotherapy. Practical guidelines are provided for choosing an antidepressant while considering efficacy, side effect profiles, and drug-drug interactions. Novel treatments for depression are also outlined, including newer antidepressants, ketamine, and allopregnanolone analogs. Common and adverse effects of these treatments are noted. Furthermore, the chapter provides recommendations for diagnosis and treatment of depression in neurology patients, specifically those with epilepsy, stroke, Parkinson’s disease, and multiple sclerosis. Throughout the chapter, a case vignette following a patient with neurological disease and depressive symptoms is examined to highlight clinical pearls. Overall, the purpose of the chapter is to discuss the importance of the neurologist’s role in screening for depressive disorders and to provide treatment recommendations. For the purpose of this chapter, the terms “depression” and “clinical depression” will be used to refer to DSM-5 depressive disorders, including major depressive disorder and persistent depressive disorder.