Inappropriately prescribed antibacterials for viral respiratory illness contribute to increased healthcare costs, unnecessary drug-related adverse effects, and drive antimicrobial resistance. The inability to rapidly and reliably distinguish bacterial from viral or non-infectious etiologies is a major impediment to appropriate antibiotic use. Pathogen detection strategies can be helpful but are limited by poor sensitivity, long time-to-result, inability to distinguish infection from colonization, or restricted number of target pathogens. A complementary diagnostic strategy focuses on the host’s response to the infection. That response is itself encompasses a highly complex biology that can be detected in the transcriptome, proteome, and metabolome among other data types. Moreover, these markers can be single biomarkers such as procalcitonin or multi-analyte biomarker panels. This presentation will review strategies to discriminate viral from bacterial infection, discussing existing as well as emerging technologies.