The etiology of respiratory infections can be elusive despite the recent advances in diagnostic technology. Thereby, the clinician needs a systematic approach for a definitive early diagnosis. This review presents the pros and cons of various invasive procedures in order to select the most appropriate diagnostic method. Expectorated sputum, the important initial step in community-acquired pneumonia, is unreliable in complex pneumonias, mainly because of colonization of the oropharynx. Even though blood cultures are frequently negative, they provide a precise diagnosis and should be obtained in undiagnosed pneumonias. Transtracheal needle aspiration has few false-negative results. However, its use has decreased because of the high frequency of false-positive cultures and risk of serious complications. Bronchoscopy provides direct access to both the bronchi and parenchyma for visualization and sampling. Plugged telescoping catheter brush, used safely in different clinical settings, has good sensitivity in identifying the pathogen, but the specificity varies with the underlying status of the patient. Because of upper airway contamination, bronchial washings are only slightly better than expectorated sputum. A newer technique, transbronchial needle aspiration, is, thus far, no improvement over the plugged telescoping catheter brush. In the immunosuppressed patient, bronchoalveolar lavage has excellent diagnostic accuracy for opportunistic infections. The accuracy increases with the addition of transbronchial biopsy. Transthoracic needle aspiration gives decisive information with low false-positive results. With the ultrathin needle, the complications decrease. Renewed interest in thoracoscopy-guided biopsy has demonstrated a high diagnostic accuracy with low complication rate. One procedure, a combination, or improvements of these procedures may reduce the need for open lung biopsy. Nevertheless, an open lung biopsy furnishes the best specimen for making a histological and microbiological diagnosis, although controversy exists regarding any improvement in survival rates.