© 2020, British Dental Association.The oral ecosystem is shaped by complex interactions between systemic health disease and the resident oral microbiota. Research in the last two decades has produced datasets describing the genetics and physiology of the host and the oral microbiome in health and disease. There are inter-individual differences in the ability to tolerate oral disease-promoting challenges. Identification of the key factors that drive a healthy and resilient oral ecosystem is urgently needed. So far, progress is being made towards replicating the host-microbiota interplay in vitro. Clinical studies may shed light on the mechanisms of oral health resilience. However, most clinical studies are cross-sectional and are insufficient for understanding resilience or for identifying biomarkers that correlate with the point of transition from oral health to dysbiosis. Mathematical and computational models, including artificial intelligence approaches, offer an opportunity to inform the design of clinical studies by identifying key biomarkers and interaction networks in complex datasets and predicting important parameters. This paper discusses some of the challenges and opportunities for understanding the biological basis of resilience of the oral ecosystem. It discusses the current status and challenges, and proposes a way forward to better understand resilience towards oral diseases.