Saliva has the potential to become a first-line diagnostic sample of choice owing to the advancements in detection technologies coupled with combinations of biomolecules with clinical relevance. Saliva is increasingly being used as an investigational aid in the diagnosis of oral and systemic diseases. It is a complex fluid containing a variety of enzymes, hormones, antibodies, antimicrobial constituents, and growth factors. Thus, saliva is functionally equivalent to serum, but its low concentration compared with serum levels in the blood may prevent salivary diagnostics from being clinically practical. However, with the development of new and highly sensitive techniques the low concentration of analytes in saliva is no longer a limitation. Evaluation of the secretions from individual salivary glands is useful for the detection of gland-specific pathology and whole saliva is used for the evaluation of systemic disorders. This review article highlights the diagnostic applications of saliva for systemic diseases and for monitoring of general health.