The diagnosis of unusual pathogens causing serious infections may be difficult. In this case report, next-generation sequencing was used in real time to diagnose a leptospirosis infection in the central nervous system, directing successful targeted antimicrobial therapy. More than half the cases of meningoencephalitis remain undiagnosed, despite extensive clinical laboratory testing. 1 – 4 Because more than 100 different infectious agents can cause encephalitis, establishing a diagnosis with the use of cultures, serologic tests, and pathogen-specific PCR assays can be difficult. Unbiased next-generation sequencing has the potential to revolutionize our ability to discover emerging pathogens, especially newly identified viruses. 5 – 8 However, the usefulness of next-generation sequencing for the diagnosis of infectious diseases in a clinically relevant timeframe is largely unexplored. 9 We used unbiased next-generation sequencing to identify a treatable, albeit rare, bacterial cause of meningoencephalitis. In this case, the . . .