This chapter provides a practical guide for clinicians evaluating patients with suspected central nervous system (CNS) infections. Emphasis is placed on common presentations, differential diagnosis, confirmatory testing, initial treatment options, and monitoring response to therapy. Acute bacterial meningitis is characterized by headache, fever, and neck stiffness. Nausea, vomiting, photophobia and seizures are common. Aseptic meningitis is a nonspecific term applied historically to patients with meningitis and negative blood and cerebrospinal cultures. Encephalitis involves brain parenchyma; fever and altered mentation are the predominant presenting symptoms. Brain abscesses are space-occupying CNS lesions which, depending on size and location, may cause focal neurological deficits. Epidural abscess is a neurological emergency. Neurological complications of HIV infection are common and have evolved with introduction of newer therapies. Patients are now living longer with HIV, and CNS pathogens have largely been replaced by HIV-associated cognitive impairment and peripheral neuropathy.