An unbiased metagenomic next-generation approach (mNGS) been shown to be useful in the broad identification of pathogens in clinical samples for infectious disease diagnosis, including viruses, bacteria, fungi, and parasites. This talk will discuss clinical licensed (CLIA) laboratory validation of a clinical mNGS assay for identification of pathogens in cerebrospinal fluid (CSF) and implementation of the automated SURPI computational pipeline for rapid analysis and interpretation of mNGS data. The CLIA-validated mNGS CSF test is now available as a clinical reference test for acutely ill hospitalized patients. We will also report the results from a 1-year, multi-hospital, nationwide study (“Precision Diagnosis of Acute Infectious Diseases”, June 2016 - 2017) to evaluate the clincail utility, performance, and cost-effectiveness of the mNGS assay relative to conventional microbiological testing in diagnosis of these neurological infections. This talk will also describe new mNGS-based technologies and diagnostic platforms in development, including host response profiling to discriminate infectious versus non-infectious etiologies, antibiotic resistance determination, and nanopore sequencing, and how these approaches can be incorporated into routine clinical diagnostic testing for infectious diseases.