Background Oral squamous cell carcinoma (OSCC) eludes all therapeutic modalities because its etiological factors, molecular mechanisms, and pathways of carcinogenesis remain controversial.
Objective This systematic review aims to identify and investigate the specific pathways commonly documented in the published research on OSCC.

Results The most frequently studied pathways in OSCC, according to the reviewed molecular studies, are p53 tumor suppressor, collective Serine/Threonine Kinases, transcription factor NF-kB, integrins and cell proliferation, vascular endothelial growth factor, Wnt signaling, the PI3K/AKT pathway, cadherins and adhesion of epithelial cells and cyclooxygenase 2 pathways. However, the MEK/ERK pathway is computationally detected as a less frequent oncogenic pathway in OSCC.
Advances in Knowledge Although the former pathways have been extensively studied, other pathways are involved in the pathogenesis of OSCC, such as Notch signaling, cell death via Fas or TNFR1 Receptors, and the p38 MAPK pathway, remain understudied in OSCC. Future studies elucidating the contribution of these pathways in the development of OSCC are urgently required.