With established applications of next-generation sequencing in inherited diseases and oncology, clinical laboratories are evaluating the use of metagenomics for identification of infectious agents directly from patient samples, to aid in the diagnosis of infections. Metagenomic next-generation sequencing for infectious diseases promises an unbiased approach to detection of microbes that does not depend on growth in culture or the targeting of specific pathogens. However, the issues of contamination, interpretation of results, selection of databases used for analysis, and prediction of antimicrobial susceptibilities from sequencing data remain challenges. In this Point-Counterpoint, Steve Miller and Charles Chiu discuss the pros of using direct metagenomic sequencing, while Kyle Rodino and Melissa Miller argue for the use of caution