The oral and maxillofacial system is responsible for vital functions such as mastication, swallowing, and breathing. Multiple biological systems including hard tissues, immune system, vasculature, nervous system, mucosal barrier and microbiome are subject to substantial crosstalk and cooperatively regulate homeostasis and disease of the oral and maxillofacial system. From a perspective of multi-system crosstalk and a viewpoint unique to dental scientist, we aim to understand the complexity of disease and biology in humans and to develop novel preventive/therapeutic strategies for various diseases.