Simple Summary: New data in the current scientific literature show that the composition of the respiratory system microbiome differs in health and disease conditions and that the microbial community as a collective entity can contribute to the pathophysiological processes associated with chronic airway disease. The respiratory microbiome is less studied than that of other areas, but it is believed to contribute to the host's local immune education and to the development of respiratory diseases, including allergies, asthma and others. In this review, was highlighted the current clinical microbiology knowledge about the microbiota and the various lung diseases relationships, previously only indirectly related to microbial pathogenesis, and the microbiota-pathogenesis relationship of lung infection, among the main causes of diseases, in order to prevent and help in a targeted treatment of various lung diseases. The recent COVID-19 pandemic promoted efforts to better understand the organization of the respiratory microbiome and its evolution from birth to adulthood and how it interacts with external pathogens and the host immune system. This review aims to deepen understanding of the essential physiological functions of the resident microbiome of the respiratory system on human health and diseases. First, the general characteristics of the normal microbiota in the different anatomical sites of the airways have been reported in relation to some factors such as the effect of age, diet and others on its composition and stability. Second, we analyze in detail the functions and composition and the correct functionality of the microbiome in the light of current knowledge. Several studies suggest the importance of preserving the micro-ecosystem of commensal, symbiotic and pathogenic microbes of the respiratory system, and, more recently, its relationship with the intestinal microbiome, and how it also leads to the maintenance of human health, has become better understood. Keywords: human microbiome; respiratory microbiome; clinical microbiology; immune modulation; dysbiosis; respiratory diseases; translational research; asthma; SARS-CoV-2