Lung cancer continues to be the number one cancer killer. Despite a surge of therapeutic advances in recent years, lung cancer remains fatal when it presents at a stage too advanced for surgical resection. In part, this is due to the disappointing reality of inevitable drug resistance in the face of highly effective, mutation-specific chemotherapy and the limited efficacy of immune checkpoint blockade. Yet, with the increasing application and integration of diverse genomic profiling approaches and the advent of high-content single-cell technologies, the mechanisms of lung cancer initiation, evolution, spread, and resistance are being unraveled at unprecedented resolution. Increasingly sophisticated mouse genetic, xenotransplantation, and ex vivo assays are also enabling functional validation and empiric screening of new therapeutic candidates. In this review, I highlight recent insights into the genetic, cellular, and molecular mechanisms of lung cancer and relate them to the normal biology of the developing and mature lung.

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