Oral cancers are the sixth most frequent cancer with a high mortality rate. Oral squamous cell carcinoma accounts for more than 90% of all oral cancers. Standard methods used to detect oral cancers remain comprehensive clinical examination, expensive biochemical investigations, and invasive biopsy. The identification of biomarkers from biological fluids (blood, urine, saliva) has the potential of early diagnosis. The use of saliva for early cancer detection in the search for new clinical markers is a promising approach because of its noninvasive sampling and easy collection methods. Human whole-mouth saliva contains proteins, peptides, electrolytes, organic, and inorganic salts secreted by salivary glands and complimentary contributions from gingival crevicular fluids and mucosal transudates. This diagnostic modality in the field of molecular biology has led to the discovery and potential of salivary biomarkers for the detection of oral cancers. Biomarkers are the molecular signatures and indicators of normal biological, pathological process, and pharmacological response to treatment hence may provide useful information for detection, diagnosis, and prognosis of the disease. Saliva's direct contact with oral cancer lesions makes it more specific and potentially sensitive screening tool, whereas more than 100 salivary biomarkers (DNA, RNA, mRNA, protein markers) have already been identified, including cytokines (IL-8, IL-1b, TNF-α), defensin-1, P53, Cyfra 21-1, tissue polypeptide–specific antigen, dual specificity phosphatase, spermidine/spermineN1-acetyltransferase , profilin, cofilin-1, transferrin, and many more. However, further research is still required for the reliability and validation of salivary biomarkers for clinical applications. This chapter provides the latest up-to-date list of known and emerging potential salivary biomarkers for early diagnosis of oral premalignant and cancerous lesions and monitoring of disease activity.