Although TNM stage is the most significant prognostic parameter in lung cancer, additional parameters are required for explaining variability of survival. Hence molecular alterations in lung cancer have been extensively studied. Most prominent among them are alterations in the p53-p21 pathway, controlling the G1/S transition. They are the most commonly observed aberrations in non-small cell lung cancer (NSCLC). The results of p53 mutations on an individual patient's changes for survival are rather controversial. In a recent study however, after analyzing p53 abnormalities both by direct sequencing and immunohistochemistry together with evaluation of bcl-2 protein expression, we have found that p53 alterations were significantly associated with poor overall survival. Recently, a more sensitive yeast functional assay for altered p53 protein has been developed, with about 70% positivity in NSCLC patients and a correlation with shortened survival. The clinical significance of p21WAF1, the protein encoded by the target gene of p53 transcription, is still controversial; however expression has been associated with favorable prognosis in squamous cell carcinoma type. The 'Rb pathway' involving two oncogenes (cyclins D and E) and two tumor suppressor genes (Rb and p16) represents another major source of molecular alterations in lung cancer. Loss of Rb does not seem to significantly influence prognosis, white loss of p16 has been show repeatedly to be a factor for poor survival. Hypermethylation of the promoter region has been proposed as an alternative mechanism for inactivation of the p16 gene. The relation between cyclin D and E expression and prognosis, still is matter of controversy. Ras mutations are reported especially in adenocarcinoma; considered alone they bear no clear relation with prognosis, in opposition when considering them together with other molecular alterations. As a conclusion, a variety of molecular markers have been implicated in the prognosis of NSCLC. However, conflicting results were reported in the literature. Thus further investigations will be required, especially the use of newer molecular assays and the development of appropriate markers or panels of molecular markers.