Saliva can be easily obtained in medical and non-medical settings, and contains numerous bio-molecules, including those typically found in serum for disease detection and monitoring. In the past two decades, the achievements of high-throughput approaches afforded by biotechnology and nanotechnology allow for disease-specific salivary biomarker discovery and establishment of rapid, multiplex, and miniaturized analytical assays. These developments have dramatically advanced saliva-based diagnostics. In this review, we discuss the current consensus on development of saliva/oral fluid-based diagnostics and provide a summary of recent research advancements of the Texas-Kentucky Saliva Diagnostics Consortium. In the foreseeable future, current research on saliva based diagnostic methods could revolutionize health care.