Systemic chemotherapy is the mainstay of treatment in patients with advanced non-small cell lung cancer. Local control of regional and metastatic lesions may be needed before systemic therapy can be started in patients with pleural effusions or bone or brain metastases. The indication for systemic chemotherapy depends on the symptoms and performance status of the patient. In addition, a risk assessment considering complications such as hemodynamic and respiratory compromise by effusions, pathological bone fractures, and neurologic deterioration caused by brain metastases is critical in selecting which patients should receive first-line systemic chemotherapy before local therapy, although predictive factors for these complications have not yet been established. Chemotherapy has been considered to have only a limited role in the treatment of patients with pleural effusions and brain and bone metastases, but recently developed anticancer agents have shown substantial antitumor effects in these types of patients with a good general condition.