Respiratory infections can be due to a multitude of etiologies and are common throughout the world. Most are viral and self-limited, yet these infections are commonly treated with antibiotics thus contributing to the increase in resistance. Historically, infectious disease diagnostics have focused on identification of the microbial culprit at the site of infection but the specificity of host response as measured by the host transcriptome, now enables us to classify the etiology of infection agnostic to pathogen class. The ability to rapidly determine whether a similar set of symptoms is due to a virus, bacteria, or other agent from a common specimen (blood) will have far-reaching public health benefits, and further research is warranted to transfer this technology into the clinical setting.