It has long been thought that respiratory infections are the direct result of acquisition of pathogenic viruses or bacteria, followed by their overgrowth, dissemination, and in some instances tissue invasion. In the last decades, it has become apparent that in contrast to this classical view, the majority of microorganisms associated with respiratory infections and inflammation are actually common members of the respiratory ecosystem and only in rare circumstances do they cause disease. This suggests that a complex interplay between host, environment, and properties of colonizing microorganisms together determines disease development and its severity. To understand the pathophysiological processes that underlie respiratory infectious diseases, it is therefore necessary to understand the host-bacterial interactions occurring at mucosal surfaces, along with the microbes inhabiting them, during symbiosis. Current knowledge regarding host-bacterial interactions during asymptomatic colonization will be discussed, including a plausible role for the human microbiome in maintaining a healthy state. With this as a starting point, we will discuss possible disruptive factors contributing to dysbiosis, which is likely to be a key trigger for pathobionts in the development and pathophysiology of respiratory diseases. Finally, from this renewed perspective, we will reflect on current and potential new approaches for treatment in the future.