Periodontal diseases are initiated by dysbiotic biofilms. The presence of a pathogenic microbial community can lead to disease initiation and progression, as well as to increased risk for future disease. In addition, because of their microbial etiology, therapies aim at controlling the biofilm. Thus, knowledge about biofilm formation, composition and function of periodontal biofilms in humans has significant importance in the treatment and prevention of periodontal diseases. Over the past several years, a number of clinical studies of the periodontal microbiome have been completed. Most of them investigated the microbiome of disease initiation, progression, treatment outcomes and risk for additional tissue breakdown. Additionally, several trials explored how systemic and environmental factors, such as smoking, diabetes and immune diseases may modulate the periodontal microbiome and influence the clinical course of periodontal diseases. In this chapter we will present the most critical clinical studies of the periodontal microbiome and discuss key aspects of their design, results and limitations, along with the clinical implications of their findings.