For most patients with head and neck squamous cell cancer, a treatment decision concerning the neck is required. Since detection of small metastases in lymph nodes is difficult, many of the patients with no detectable metastases receive elective treatment of the neck. Additional information on the metastatic potential of the primary tumor before treatment may be useful to reduce the number of these elective procedures. Biomarkers may supply such information. Molecules involved in several pathways have been studied, but the complexity of the metastatic process makes it unlikely that a single marker for metastasis can de identified. Techniques allowing the study of many factors simultaneously seem to be the most promising ones. In recent years, microarray expression profiling and comparative genomic hybridization studies have yielded interesting results. If these results can be confirmed in larger studies, they may play a role in future clinical decision making on treatment of the clinically N0 neck.