Lower respiratory infections are the major cause of death due to infectious disease in the United States and worldwide. Most forms of community-acquired pneumonia (CAP) are treatable, and there is consensus that the selection of antimicrobial agents is notably simplified if the pathogen is defined. The rich history of CAP studies in the prepenicillin era showed that an etiologic diagnosis was established in >90% of cases, but the 2009 data from Medicare indicate that a probable pathogen is now detected in <10% according to a review of the records of >17,000 patients hospitalized with CAP. This review addresses the issue of the state of the art of microbiological studies of CAP in terms of the realities of current-day practice. Unfortunately, the desire for better data to achieve pathogen-directed treatment clashes with a multitude of harsh realities, including cost, Centers for Medicare and Medicaid Services (CMS) requirements for antibiotics to be administered within 6 h of disease onset, guidelines that discourage any microbiological studies in most cases, belief in empiricism that is well supported by at least 1 prospective study, the decline of microbiological analysis standards in most laboratories, and the devastating impact of the Clinical Laboratory Improvement Amendments (CLIA) regulations that led to the demise of "the house staff laboratory" and the distancing of microbiological analysis from the site of care. Microbiological principles are reviewed, with emphasis on specimen source, pathogenic potential of isolates, concentrations, impact of antecedent antibiotics, and the "Washington criteria" for expectorated sputum. The recommendation is that the high-quality microbiological analysis that is still achieved in some places should be retained but that to advance the field on the basis of the contemporary realities, two goals should be adopted: First is the broad use of antigen tests for Streptococcus pneumoniae and Legionella pneumophila with interpretation by clinical staff under the CLIA waiver for low-complexity tests. The second and more ambitious recommendation is the adoption of molecular techniques, with particular emphasis on nucleic acid detection, which is rapid and sensitive and has already been developed for virtually all recognized pulmonary pathogens. This may be the ultimate solution for many laboratories, and it is likely to have selected use.