In this article of EBioMedicine, Santosh Renuse and colleagues 1 show the relevance of combining immunoaffinity capture with targeted mass spectrometry measurement to detect SARS-CoV-2 nucleocapsid proteins in nasopharyngeal swab samples. The COVID-19 pandemic has confirmed the need to improve the toolbox available to diagnose respiratory infections. Rapid, reliable, and highly specific detection is essential if we are to mount immediate preventive and therapeutic responses. This report stands out from previous studies as it implements immunocapture along with robust validation for a large cohort of subjects. The results presented show that mass spectrometry is definitively at a crossroads for large-scale clinical applications.