Failure of the treatment in head and neck cancer is connected with local and distal tumor metastases, local recurrence and formation of second primary tumors. Clinical procedures have a limited applicability to a prediction a further progression of the tumor. Hence an attention has turned towards molecular and subcellular analyses. It is not clear yet, which of the analyses would provide a better prognostic information, that in primary tumor itself or in the histologically normal surgical margin. An informative potential of the analysis of TP53 gene mutations, hypermethylation of promoters of the chosen genes and instability of microsatellite sequences for disease prognosis is reviewed. While TP53 mutation profile and gene expression appear to be the most reliable prognostic factors, the limitations of using the molecular techniques are discussed.