Lung carcinogenesis is considered to be the result of composite environmental, genetic and epigenetic changes. Despite the fact that many of the genetic alterations, including loss of heterozygocity in the 3p chromosome locus and point mutations in the tumor-suppressor genes TP53 and retinoblastoma (RB1), occur in nearly all histopathologic types of lung cancer, the frequency and the "timing" of their occurrence seems to differ between small-cell lung cancer (SCLC) cells, that are characterized by neuroendocrine differentiation, and non-small-cell lung cancer (NSCLC) cells. Although loss of cell-cycle control is the crucial molecular event in both types, the mechanism by which it provokes oncogenesis differs significantly between SCLC and NSCLC. Importantly, some of these molecular events, including DNA-damage response and epidermal growth factor receptor (EGFR) mutations are valuable in predicting response to conventional chemotherapy or molecular-targeted agents as well as in the prognosis of patients that harbor these alterations. In the current review we report on the best characterized histopathologic and genetic changes in NSCLC and SCLC in relation to each histological subtype and we discuss their predictive and prognostic implications.