Novel strategies are needed to improve outcomes for patients with LA SCCHN. Enhancing chemoradiation by targeting Inhibitor of Apoptosis Proteins (IAPs) – a class of proteins that regulate apoptosis and modulate immune responses – is currently the most promising strategy, and a phase III clinical trial is underway. Alternative targeted therapies in combination with (chemo)radiation are also being investigated. Dr. Yungan Tao, Dr. Jonathan Schoenfeld, and Dr. Ezra Cohen review the available data for targeting IAPs and consider the future treatment landscape for patients with LA SCCHN.