Head and neck cancers (HNCs) include several cancers originating in the upper airways that represent a variety of histologies. The most common type of HNC is squamous cell carcinoma (SCC), which is linked to tobacco and alcohol use and to human papilloma virus (HPV). At present, there are no standard molecular tests that are routinely used in clinics. This overview will discuss the current knowledge on molecular markers with the potential to be developed as diagnostic tests for cancer risk assessment, early detection, clinical response prediction to specific therapies, and prognosis. These markers are usually based on recent findings in tumor biology and genetic defects in HNC, and provide information both independently and in combination with currently available clinical parameters. In practice, many potential markers are difficult to measure due to assay variability, lack of standards for the interpretation of assay results, and incomplete knowledge of the effects on disease biology and response to treatment. However, there is great enthusiasm for the general concept of using molecular knowledge for the clinical management of HNC. Although it will be a great challenge to develop robust and reliable molecular diagnostic tests, the development of promising assays fueled by advances in science and technology will continue and will ultimately reach the goal of improving the care of HNC patients.