Health care- and device-associated central nervous system (CNS) infections have a distinct epidemiology, pathophysiology, and microbiology that require a unique diagnostic approach. Most clinical signs, symptoms, and tests used to diagnose community-acquired CNS infections are insensitive and nonspecific in neurosurgical patients due to postsurgical changes, invasive devices, prior antimicrobial exposure, and underlying CNS disease. The lack of a standardized definition of infection or diagnostic pathway has added to this challenge. In this review, we summarize the epidemiology, microbiology, and clinical presentation of these infections, discuss the issues with existing microbiologic tests, and give an overview of the current diagnostic approach.