Acute respiratory infection (ARI) is a common diagnosis in outpatient and emergent care settings. Currently available diagnostics are limited, creating uncertainty in the use of antibacterial, antiviral, or supportive care. Up to 72% of ambulatory care patients with ARI are treated with an antibacterial, despite only a small fraction actually needing one. Antibiotic overuse is not restricted to ambulatory care: ARI accounts for approximately 5 million emergency department (ED) visits annually in the USA, where 52–61% of such patients receive antibiotics. Thus, an accurate test for the presence or absence of viral or bacterial infection is needed. In this review, we focus on recent research showing that the host-response (genomic, proteomic, or miRNA) can accomplish this task.