Biomarkers are broadly classified as genomic, proteomic, or metabolomic. Molecular biology and oncology research studies on oral cancer biomarkers focus on identifying key biological molecules or markers that could be linked to cancer development, risk assessment, screening, recurrence prediction, indicating prognosis, indicating invasion/metastasis and monitoring therapeutic responses of cancer. Cluster of differentiation factor 34 is a salivary biomarker that can identify recurrence potential of oral squamous cell carcinoma (OSCC). Integrin α3 and integrin β4 are genomic biomarkers that are helpful in estimating the risk of regional and hematogenous dissemination of malignant oral squamous cells. Other examples are vascular endothelial growth factor, B-cell lymphoma-2, claudin 4, yes-associated protein 1 and MET proto-oncogene, and receptor tyrosine kinase, which are genomic biomarkers that are used to predict radio-resistance in OSCC tissue. The present article reviews the clinical application, methodologies and steps in developing candidate biomarkers, protocols in reporting, evaluating candidate biomarkers, and challenges in biomarker research with a focus OSCC.