Intratumoral heterogeneity (ITH) dynamics in small cell lung cancer (SCLC) are poorly understood, and studying ITH evolution may inform novel therapies aimed at halting SCLC progression. In their study on page 892, Wollenzien and colleagues assessed SCLC ITH dynamics using adenoviral lineage barcodes and single-cell RNA-sequencing in SCLC transgenic mouse models as well as SCLC cell lines and xenografts. Subclonal analysis revealed increasing expression of AP-1 transcription factors during tumor progression and of cancer testis antigens in response to chemotherapy. More broadly, the authors used subclonal analyses to interrogate clonal selection events and SCLC cell plasticity over the course of tumor progression and chemotherapy. The cover features a single-cell RNA-sequencing UMAP dimensionality reduction plot, with which the authors performed cluster analysis and demonstrated that chemotherapy enhances SCLC cell plasticity. This article is also Highlighted on page 865.