Central nervous system (CNS) infections require early recognition and aggressive management to improve patient survival and prevent long-term neurologic sequelae. Although early detection and treatment are important in many infectious syndromes, CNS infections pose unique diagnostic and therapeutic challenges. The nonspecific signs and symptoms at presentation, lack of characteristic infectious changes in laboratory and imaging diagnostics, and closed anatomic and immunologically sequestered space each present challenges to the emergency physician. This article proposes an approach to the clinical evaluation of patients with suspected CNS infection and highlights methods of diagnosis, treatment, and complications associated with CNS infections.