With approximately 500,000 new cases annually, squamous cell carcinomas of the head and neck (HNSCC), represent one of the six most common cancers in the world. This disease, which includes malignant lesions arising in the oral cavity, larynx and pharynx, results in nearly ~11,000 deaths each year in the United States alone. The five-year survival rate after diagnosis for HNSCC remains low, approximately 50%, which is lower than that for other frequent cancers types, such as colorectal, prostate, and breast cancer. This poor prognosis is largely due to the advanced nature of the disease at the time of diagnosis, and the limited response to currently available treatment options. Recent discoveries have provided unprecedented opportunities to understand how the dysregulated function of signaling networks contributes to the initiation, malignant growth, and metastatic spread of HNSCC. This information is now being exploited to identify novel mechanism-based preventive strategies and anti-cancer therapies. Indeed, recent focused efforts have revealed that activation of the signaling molecule mTOR is an early and one of the most frequent events in HNSCC. Remarkably, the blockade of mTOR with its specific clinically-relevant inhibitors, such as rapamycin, provokes the death of HNSCC cells and tumor regression in all experimental oral cancer model systems tested, including those involving HPV-associated HNSCC. mTOR inhibition displays potent anti-lymphangiogenic activity, and prevents the metastatic spread of HNSCC cells to locoregional lymph nodes thereby prolonging animal survival. We have also observed recently that the mild inhibition of mTOR by the use of metformin can prevent the progression of oral premalignant lesions to HNSCC. These striking findings have provided a strong rationale for launching a multi-institutional effort aimed at investigating the clinical efficacy of mTOR inhibitors as a molecular-targeted option for HNSCC cancer prevention and treatment. The molecular mechanisms underlying the remarkable effects of mTOR inhibitors in HNSCC and other cancer types will be discussed.