Viral infection represents a common and problematic health care issue, particularly in younger and senior populations. The respiratory tract is a major portal for microbial exposure, where viral infection can result in nonsymptomatic, mild, and self-limiting or severe and sometimes fatal infection. Although it is well established that virus-specific properties, such as longevity and replication kinetics, impact clinical manifestations, it is less well understood why distinct infectious outcomes may occur across a population of individuals infected with the same strain of virus. Emerging evidence points to interpersonal variation in pulmonary and gastrointestinal microbiome composition, and specifically to members of the Lactobacillus genus, as key components in defining respiratory viral infection outcomes. Moreover, human studies of airway microbiota after pH1N1 demonstrate that the composition of the respiratory microbiome can be modified by viral infection in a manner that enriches for pathogens associated with secondary bacterial infection. In this article, current knowledge in the field of human microbiome research, particularly as it pertains to respiratory viral infection, is reviewed.