Performance status2 (PS2) patients represent a significant proportion of the advanced non-small cell lung cancer (NSCLC) population who in the large part have been under-represented in clinical trials. The optimal treatment regimen for this group of patients is still under debate mainly because their enrollment either in trials of first-line treatment for advanced disease is practically non-existent or limited at the very best. The emphasis in these patients' care should be on maintenance and improvement of quality of life (QOL) with treatment strategies that provide rapid clinical improvement. On the basis of current evidence, chemotherapy appears justified to patients with advanced NSCLC and a PS of 2. The choice of the drug should be based on the toxicity profile of each agent and type of co-morbid conditions. Additional studies are needed in order to evaluate the future perspectives of the molecular targeted agents in the treatment of PS2 patients.