The 2021 World Health Organization (WHO) classification system for thoracic tumors (including lung cancer) contains several updates to the 2015 edition. Revisions for lung cancer include a new grading system for invasive nonmucinous adenocarcinoma that better reflects prognosis, reorganization of squamous cell carcinomas and neuroendocrine neoplasms, and description of some new entities. Moreover, remarkable advancements in our knowledge of genetic mutations and targeted therapies have led to a much greater emphasis on genetic testing than that in 2015. In 2015, guidelines recommended evaluation of only two driver mutations, ie, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions, in patients with nonsquamous non-small cell lung cancer. The 2021 guidelines recommend testing for numerous additional gene mutations for which targeted therapies are now available including ROS1, RET, NTRK1-3, KRAS, BRAF, and MET. The correlation of imaging features and genetic mutations is being studied. Testing for the immune biomarker programmed death ligand 1 is now recommended before starting first-line therapy in patients with metastatic non-small cell lung cancer. Because 70% of lung cancers are unresectable at patient presentation, diagnosis of lung cancer is usually based on small diagnostic samples (ie, biopsy specimens) rather than surgical resection specimens. The 2021 version emphasizes differences in the histopathologic interpretation of small diagnostic samples and resection specimens. Radiologists play a key role not only in evaluation of tumor and metastatic disease but also in identification of optimal biopsy targets. ©RSNA, 2024 Test Your Knowledge questions in the supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.