Abstract: Transformed small cell lung cancer (SCLC) represents a rare but lethal form of acquired resistance that occurs in approximately 5% of patients with non-small cell lung cancer (NSCLC) undergoing targeted or immune therapy. Most transformed SCLC are derived from epidermal growth factor receptor (EGFR)-mutant lung adenocarcinomas arising after a median interval of 19 months. Median overall survival after transformation is only 6 months. Repeat biopsy combined with next-generation sequencing or droplet digital polymerase chain reaction remains the gold standard diagnostic method. Serum pro-GRP, whole-genome doubling, copy-number burden, and concurrent RB1/TP53 alterations are promising predictive biomarkers. Pathogenesis involves RB1/TP53 inactivation, dysregulated PI3K-AKT and NOTCH signaling, MYC amplification, and SOX mutations, all of which contribute to driving transformation. Responses to platinum etoposide chemotherapy (the front-line regimen) are transient. Combining with anti-angiogenic agents or local radiotherapy may prolong overall survival. Emerging strategies targeting DLL3 or EZH2 are promising. This review summarizes the latest evidence on clinical presentation, diagnostic strategies, molecular underpinnings, and therapeutic advances to guide future clinical investigations and translational research.