The two most important scientific developments of the past decade regarding therapies for patients with non-small cell lung cancer are the ability to exploit particular genetic mutations with targeted therapies and the discovery of drugs that can help the patient’s own immune system attack the cancer. Despite these advances, many patients do not yet benefit from either approach. To maximize patient benefit, clinicians and pathologists will need to rationally apply the growing scientific knowledge to best characterize a patient’s tumor and possible driver mutations. A growing understanding of host-tumor immune interactions will hopefully help expand our therapeutic options. Lastly, the still elusive identification of immunotherapy biomarkers will hopefully help identify patients most likely to derive a therapeutic response to immune checkpoint inhibitors, and promises to be an important field of study for years to come.