The genus Prevotella comprises of a diverse set of gram-negative anaerobes that are implicated in both health and disease. Prevotella is a common human commensal of various anatomic sites but can also be associated with the dysbiotic microbiomes of various chronic inflammatory diseases. Due to it’s association with both commensalism and disease, the role of Prevotella in disease progression is unclear. However, Prevotella has shown immunomodulatory potential, the ability to change the metabolic microenvironment and other cytotoxic phenotypes in both in vitro and in vivo studies. Despite this, Prevotella remains understudied both at the genomic and phenotypic levels. In this thesis, we explore the role of Prevotella in the context of the cystic fibrosis lung microbiome. In this thesis we characterize the ecological composition of a longitudinal pediatric CF cohort called EcoCF and show that the prevalence and relative abundance of Prevotella remains relatively stable from mild to severe lung disease. Prevotella is often the dominant species in samples of higher bacterial diversity, which is associated with higher lung function but is also differentially enriched in samples of lower lung function, where bacterial diversity is low. We attempt to explain this contradictory result by exploring the genomic diversity in the genus Prevotella, with a focus on P. melaninogenica and its closely related species that are often associated with the CF lung. We show that P. melaninogenica is a complex of species with varied potential for horizontal gene transfer. Prevotella species have high recombination rates but also complex restriction-modification systems. Our work highlights the incredible genomic diversity within some of the oropharyngeal commensal Prevotella, indicating that the key to drawing meaningful associations of Prevotella with health and disease is by studying the genus Prevotella resolved at the strain-level.