Lung cancer is the most common cause of cancer-related death worldwide, owing to its metastatic spread at the time of diagnosis. As a result, chemotherapy is the standard of care for the majority of patients. In recent years, the role of chemotherapy has expanded to include maintenance therapy and approved second-and third-line treatments. Nonetheless, traditional chemotherapy has modestly improved outcomes in patients with advanced non-small-cell lung cancer (NSCLC). Research efforts have been redirected toward the integration of molecularly-targeted agents into a treatment algorithm with unprecedented survival rates in selected patients. This article will provide an update on the multiple systemic regimens available to treat NSCLC, and discuss emerging molecular-based therapies