Background: Oral squamous cell carcinoma (OSCC) represents most of the cases of neoplasms of the mouth and still keeps low survival rates. The usefulness of this dysplasia subdivision has been questioned to predict the risk of malignant transformation; consequently, one of the biggest challenges is to predict which lesions will progress to OSCC. Methods: A comprehensive search of the literature was carried out using the following terms: (biomarker) OR (markers) AND (oral potentially malignant disorders) OR (oral squamous cell carcinoma) OR (oral leukoplakia) OR (proliferative verrucous leukoplakia), and (OSCC) OR (OPSCC) AND (HPV). Also, using the mesh tool with terms: (biomarker) AND (squamous cell carcinoma of head and neck) OR (leukoplakia, oral). A total of 138 documents were chosen, including consensus workshops, books, observational and longitudinal studies, systematic reviews, and meta-analyses. Results: The tumor microenvironment compounds a functional ecosystem of tumor cells. The main molecules involved are cytokines and immunophenotypes of antigens, which can promote the immunoediting process. Several studies associate IL4R, CD163, MPO, CRP, CD68, MRC1, MMP-9, IL-8, IL-6, TNF-α, IL-1β, IL-10, IL-13, IL-1RA, COX-2, CD3, PDPN, CD34, and IL-1α with the development of OSCC, and some of these were linked with oral potentially malignant disorders. Conclusion: Currently, there are no biomarkers clinically validated, notwithstanding, the recognition of these molecules as biomarkers can enhance new tools for early diagnosis alongside new treatments. Take-home message: OSCC can be preceded by molecular shifts that corrupt the immune system paths and these changes cannot be seen through histopathological assessment; thus clinical behavior and prognosis of those lesions can be underestimated.