Great advances have been made in chemotherapy in advanced and metastatic non-small-cell lung cancer (NSCLC), and a major milestone was reached with the administration of neoadjuvant chemotherapy in stage IIIA N2 disease. The systemic nature of lung cancer has been confirmed by many genetic analyses documenting micrometastases in negative lymph nodes and bone marrow, and mRNA gene overexpression as a surrogate of cancer cells has been identified in peripheral blood. Furthermore, serum or plasma cell-free tumor DNA has been observed even in tumors with a diameter of less than 2 cm. Pharmacogenetic screening can lead to tailored chemotherapy even in patients with early disease through the use of a genetic tool kit that will allow us to optimize the use of chemotherapy by using serial measurements of serum DNA that can help to detect residual disease and re-assess the chemosensitivity of sub-clinical micrometastatic disease. The ongoing (neo)adjuvant taxol/carboplatin hope (NATCH) trial is testing the value of three cycles of chemotherapy given pre- or post-operatively compared with surgery alone and will analyze genetic abnormalities in serum DNA at three different points during patient follow-up. Our major concern in this review is to analyze the pros and cons of chemotherapy in NSCLC. Although this review is not a formal meta-analysis, we have discussed the most relevant published studies in this field. We conclude that not only is there no evidence of detrimental effects of chemotherapy, in fact, there are many indications that chemotherapy induces response in up to 80% of patients and downgrades N2 disease in up to 50% of patients. This translates into significantly better survival when accompanied by complete resection. Since at least 50% of patients with stage IB disease develop distant metastases, it seems logical to explore the role of chemotherapy in early disease.