Patients with poor performance status (PS) and advanced lung cancer have been underrepresented in clinical trials. As a consequence, the management of these patients in clinical practice is often empirical. Recent data indicate that patients with advanced non-small cell lung cancer (NSCLC) and a PS of 2 tend to benefit from first line chemotherapy with respect to symptom improvement and perhaps overall survival. Whether single-agent or combination chemotherapy is preferable remains debatable. In previously treated patients with NSCLC, EGFR tyrosine kinase inhibitors produced a substantial rate of clinical benefit and led to an improvement in survival compared with placebo in studies that included a significant percentage of patients with poor PS.