Oral biofilms are complex microbial communities that colonize various surfaces in the mouth, including teeth, oral mucosa, and dental prostheses. These biofilms are influenced by host and environmental factors like diet, saliva, and oral hygiene, which can disrupt the microbial balance and lead to oral diseases such as dental caries. This chapter focuses on the clinical studies that investigate caries-related oral biofilms, especially supragingival dental plaque. The cariogenic potential of dental plaque is attributed to multiple factors including plaque accumulation, pH levels, microbial and mineral composition. The interplay of these factors is essential for predicting and managing caries. This chapter also discuss clinical studies that have identified certain microorganisms, such as Streptococcus mutans and Candida species, which are more prevalent in carious conditions. These organisms exhibit traits such as acid production and survival in acidic conditions, which enhance their virulence in dental caries development. Advanced methodologies, including next generation sequencing and spatial imaging, have revolutionized the understanding of the oral microbiome, allowing for a deeper analysis of its role in tooth decay. Despite significant advances, current clinical research faces limitations like small sample sizes, lack of diversity in study populations, and a focus on specific microbial species. The chapter calls for more comprehensive, longitudinal studies that consider the full spectrum of the microbiome, including fungi and viruses. Future research aims to employ novel imaging techniques to explore the spatial structure of dental plaque, which could offer new insights into microbial interactions and their impact on oral health.