Recent data on the use of immunotherapy and targeted treatments in patients with advanced non-small cell lung cancer (NSCLC) have introduced a myriad of questions. These include controversial topics and difficult decisions, like when to incorporate CTLA-4 inhibition and what patients can expect from immuno-oncology monotherapy in the metastatic setting. Edward B. Garon, MD, MS, professor in the department of medicine in hematology/oncology and director of the thoracic oncology program at the Jonsson Comprehensive Cancer Center at the University of California Los Angeles, discusses key challenges in NSCLC care with Robert A. Figlin, MD, the Steven Spielberg Family Chair in Hematology-Oncology at Cedars-Sinai Cancer Center in Los Angeles. From optimal strategies in second-line settings to promising clinical trials, Dr. Garon shares how he applies emerging information in practice.