Carcinoma of the lung is the most common cause of cancer-related death in men and women. Prognosis correlates strongly with stage of disease at presentation and to some degree with the histological subtype of the tumor. Histological classifications of lung cancer were somewhat arbitrary and a matter of convenience. However, multiple lines of differentiation are often found within a single tumor, if it is sufficiently sampled. The new therapeutic approaches especially of non-small cell lung cancer place high demands on pathologists: a clear histological diagnosis with information on the predominant histological subtype is required, obtained by using additional immunohistochemical methods. Using molecular methods, predictive and prognostic factors for adjuvant and neoadjuvant therapies can be identified in tumor cells of small cell lung cancer and non-small cell lung cancer. Biological and molecular factors known in this regard include the epidermal growth factor family and its receptors, K-RAS mutations, neuroendocrine tumor differentiation, and nucleotide-excision-repair proteins (ERCC1 and RRM1). Thymidilate synthase is an interesting target for anticancer agents such as the antifolate pemetrexed. Given the aspect of individualized lung cancer therapy, the collective term small cell/non-small cell lung cancer introduced by the groups of Chuang in1984 and Thomas in 1993 can be regarded as no longer sufficient. Copyright (C) 2010 S. Karger AG, Basel