Spinal cord infections pose urgent diagnostic and management issues. This article outlines a clinical approach to potential spinal cord infection based on demographic risk factors and both central nervous system (CNS) and extra-CNS clinical clues. The spectrum of disease in vulnerable patient groups, such as transplant and chemotherapy recipients, patients infected with the human immunodeficiency virus, and international travelers, is discussed. Serologic and cerebrospinal fluid investigations for bacterial, viral, and parasitic spinal cord infections are outlined with accompanying characteristic magnetic resonance imaging and other images. Clinical, epidemiologic, and initial management strategies for important spinal cord infections conclude the discussion.