This chapter summarizes the recent advancement of our knowledge of the healthy oral microbiome, and address the potential role of the oral microbiome in systemic diseases, including cardiovascular disease and pneumonia. An understanding of the composition of the oral microbial community with respect to oral health is essential for diagnosis, prevention, and treatment of oral diseases. The chapter describes oral microbiome associated with periodontal disease, microbiome associated with endodontic infections, apical periodontitis and tooth decay, and oral microbiome associated with oral cancer. Diseases caused by the oral microbiome are not limited to oral infections. Recognition that disease conditions associated with the oral microbiome contribute to systemic infections may require clinicians to consider alternative preventative and therapeutic approaches. The current data on two of the most-studied systemic conditions, cardiovascular and respiratory diseases are reviewed in the chapter. A community-and microbial ecology-based pathogenic concept that forms the basis for understanding relationships between the oral microbiome and the host, as well as developing novel strategies for therapeutics and disease prevention is discussed in the chapter. A better understanding of the oral microbiome structure and function and the dynamics between the commensals and pathogens is needed to selectively modulate composition of the microbiome and prevent oral disease.