Early effective and accurate antibiotic therapy is the key to reduce mortality of patients with severe infections. Identification of pathogenic microorganism is essential for appropriate antibiotic therapy. Metagenomics next generation sequencing (mNGS) is a novel pathogenic, diagnostic technology with fast detection speed, high accuracy, and comprehensive coverage. mNGS has been used to diagnose specific pathogenic microbial infections in recent years. However, many problems still need to be solved in the early target anti-microbial therapy of severe infections. This paper summarizes several problems that need to be considered in the use of mNGS in severe cases.