The capability to assess physiological states, detect morbidity initiation and progression, and monitor posttreatment therapeutic outcomes through a noninvasive approach is one of the most desirable goals for healthcare research and delivery. Saliva, a multi-constituent oral fluid, has high potential for the surveillance of general health and disease. To reach the above goal through saliva-based diagnostics, two prerequisites must be fulfilled: (1) discovering biomarker(s) for different diseases among the complicated components of saliva, and (2) advancing sensitivity and specificity of biomarker(s) through persistent development of technologies. Under the support and research blueprint initiated by the National Institute of Dental and Craniofacial Research (NIDCR), salivary diagnostics has not only steadily progressed with respect to accuracy and availability, but has also bridged up-to-date nanotechnology to expand the areas of application. With collective efforts over several years, saliva has been demonstrated to be a promising bodily fluid for early detection of diseases, and salivary diagnostics has exhibited tremendous potential in clinical applications. This review presents an overview of the value of saliva as a credible diagnostic tool, the discovery of salivary biomarkers, and the development of salivary diagnostics now and in the future.