With their ability to produce antibiotics, influence drug transport, and serve as vehicles or adjuvants for drug delivery, microbial signatures may provide new information on the pathophysiology of different lung illnesses. Most investigations of lung microbiome signatures were previously conducted using bronchoalveolar lavage (BAL) fluid and usually required bronchoscopy, a technique that involves passing an optical device through the airways to visualize the tracheobronchial tree. In the context of lung illnesses, this method is a multipurpose modality with diagnostic and therapeutic potential. To diagnose lung illness using bronchoscopy samples, we conducted a comprehensive literature search to identify clinical trials that evaluated the use of microbial signature analysis using polymerase chain reaction (PCR). Only 17 of the 1,784 studies met the inclusion criteria. The effect of pulmonary microbiota on the outcome of lung disease has been the subject of few studies. The data and results indicated that microbial signatures are significantly associated with lung disease. Despite conflicting findings, bronchoscopy-based analysis of lung microbiome signatures for lung disease diagnosis and prognosis remains a promising new area of treatment. Analysis of lung microbial signatures opens the door to the possibility of restoring native microorganisms and treating dysbiosis by manipulating the composition of the lung microenvironment.