In recent years we have witnessed several significant developments in the treatment of advanced non-small cell lung cancer (NSCLC). As the number of therapeutic options for advanced NSCLC has increased, treatment decisions for medical oncologists and patients have become more complicated, a shift from the nihilism that dominated lung cancer therapeutics in the past. In this issue of the Open Lung Cancer journal, we review four “hot topics” in the management of advanced NSCLC: 1) targeting of angiogenesis, 2) epidermal growth factor inhibitors, 3) maintenance therapy, and 4) the clinical significance of histologic subtype.