The disappointing results of long-term survival among patients with non-small cell lung cancer (NSCLC) may reflect the lack of knowledge of the ways in which molecular abnormalities of neoplastic cells affect responsiveness to anticancer therapy. Remarkable advances in the understanding of NSCLC cancer biology have been made over the past decade, including the discovery of critical mutations in oncogenes (i.e., mutation of K-Ras and c-myc gene), as well as the loss of tumor-suppressor genes, such as TP53, 16INK4, or Rb. The future challenge of NSCLC chemotherapy relies on the identification of molecular markers that are predictive of drug sensitivity and help in the selection of chemotherapeutic agents best suited to the individual patient. Other intriguing issues will be the identification of the optimal drug sequence in combination regimens, as well as polymorphisms of genes involved in severe toxicities.