The classification of lung cancer has always been primarily based on the morphologic assessment of routinely stained histological sections, but this approach may be difficult or even unfeasible in cytological preparations or small biopsies. Moreover, the simplistic dichotomization between small-cell carcinoma and non-small cell carcinoma (NSCLC) should be overcome, as new drugs have been discovered that are effective in specific subtypes of lung cancer. A more accurate characterization of NSCLC, however, may be hard in carcinomas lacking clear-cut signs of differentiation. The incorporation into the diagnostic algorithm of poorly differentiated carcinomas of an immuno-histochemical panel including markers of squamous (high-molecular-weight cytokeratins, p63) and glandular (TTF-1, cytokeratin 7) cell differentiation seems the most promising approach. The evaluation of lung cancer for gene mutations, gene amplification, tumor-related angiogenesis, expression levels of DNA repair genes and genomic or proteomic profiles represents an exciting challenge for the pathologist in the near future.