Background: The first step in a biomedical investigation of a disease entity involves framing a research hypothesis. The hypothesis is framed based on the pre-existing information. Evidence for the hypothesis is usually gathered starting with epidemiological studies to estimate the prevalence, etiology, associated risk factors of the disease. Once an epidemiological association is established then the investigation involves the use of experimental (in vivo, in vitro) studies to decode the molecular biology of the disease based on which we can formulate appropriate interventions. The major limiting factors in this approach is translating the data obtained from experimental studies on to clinical trials. These limitations are because of the inability of the in vivo and in vitro studies to replicate the microenvironment of the disease in humans. Experimental studies capable of closely simulating disease environment in humans would aid in eliciting the true nature of these diseases. At present, mouse models are largely being used to study human diseases including cancer. Aim and clinical significance: Although mouse models are considered better than other experimental models, it is vital that researchers select appropriate mouse models which would suit the purpose of the study. Thus, the present manuscript aims to critically review the applications and limitations of all mouse models employed in oral oncology which may aid the researchers in selecting the most optimal mouse models for their respective research.