Optimal management of lower respiratory tract infection relies on distinguishing infectious from noninfectious etiologies and identifying the microbiologic cause if applicable. This process is complicated by overlapping clinical symptoms and the colonizing lung microbiota. In a recent issue of the JCI, Mick, Tsitsiklis, and colleagues apply RNA-Seq to tracheal aspirates from critically ill children and demonstrate how integration of the host response with microbial identification results in a harmonious and accurate diagnostic classifier. Though promising, there are numerous barriers to realizing a combined host and pathogen diagnostic.