As described elsewhere in this issue [2, 3] , microbiological evidence of infection must be considered in the context of several fundamental difficulties found in respiratory diagnostics, including the frequent lack of access to the site of infection, the insensitivity of available tests, insufficient assay validation, and complexities in determining whether a detected pathogen has a causal role in the illness. The specific research-related demands of PERCH added to these constraints, requiring that our diagnostic strategy must exclude any prior assumptions regarding the likely importance of specific pathogens; must include a full range of respiratory tract specimens, including upper respiratory swab or aspirate, induced sputum, lung aspirate, bronchoalveolar lavage, and pleural fluid; must be comprehensive, yet realistic; must appropriately balance the demands of accuracy and efficiency; must account for both clinical and research ethical issues; and must be feasible for use and support at all participating field sites.