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Cell cycle is a complex and coordinated process characterized by orderly progression in the life cycle of cells mainly orchestrated by cyclins and cyclin dependent kinases (CDK) and their inhibitors. The kinases drive the cell cycle by phosphorylating critical target proteins that are required for progression of cell to the next phase of cell cycle.  This progress is tightly regulated by a group of cell cycle inhibitors known as CDK inhibitors which may be responsible for maintenance of cell cycle and proliferation arrest once the cells’ developmental fate has been reached. Cell cycle inhibitors may act as checkpoints to identify the defective components of the cell thereby aiding in its repair and hence inactivation of these genes may interfere with the terminal differentiation thus leading to unrestricted proliferation and tumorigenesis. Cell proliferation is an important property of malignant tumor cells and dysregulation of genes governing the cell cycle is of considerable significance in the development of oral squamous cell carcinoma. Most OSCC generally develop by the malignant transformation of potentially malignant disorders the most common of which is leukoplakia. Hence evaluation of these genetic alterations in leukoplakia can be useful in assessment of the potential for malignant transformation and may also aid in attempting any therapeutic strategies at this stage. This review aims to provide data related to the role of cell cycle inhibitors in oral leukoplakia highlighting their role in malignant transformation.