Oral squamous cell carcinoma (OSCC) is one of the most common human malignancies with complex etiology and poor prognosis. Although environmental carcinogens and carcinogenic viruses are still considered the main etiologic factors for OSCC development, genetic factors obviously play a key role in the initiation and progression of this neoplasm, given that not all individuals exposed to carcinogens develop the same severity of the disease, if any. Identifying genetic loci modulating OSCC risk may have several important clinical implications, including early detection, prevention and developing new treatment strategies. Due to limitations in controlled and standardized genetic studies in humans, genetic components underlying susceptibility of OSCC development remain largely unknown. A combination of quantitative trait loci mapping in mice, with complementary association studies in humans, has the potential to discover novel cancer risk loci. As of today, a limited number of genetic analyses were applied on rodent models to locate novel genetic loci associated with human OSCC. Here, we discuss the current status of the mouse models use for dissecting the genetic basis of OSCC and highlight how systems genetics analysis using mouse models, may increase our understanding of human OSCC susceptibility.