This study investigates the evolutionary processes underlying the high sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse. By analyzing 160 tumors from 65 patients using multiregion sequencing, the researchers found that treatment-naive SCLC exhibited clonal homogeneity at distinct tumor sites, while first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. Branched evolution and a shift to ancestral clones were observed, leading to tumor relapse. Effective radiotherapy or immunotherapy induced the re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. *TP53* and *RB1* alterations were exclusively part of the common ancestor, while *MYC* family amplifications were not always present in the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumors with clonal *CREBBP/EP300* alterations underwent genome duplications. Gene-damaging *TP53* alterations and co-alterations of *TP73*, *CREBBP/EP300*, or *FMN2* were significantly associated with shorter disease relapse following chemotherapy. The study highlights the importance of the common ancestor in driving clonal diversity at relapse and identifies key genomic patterns associated with sensitivity and resistance to chemotherapy.This study investigates the evolutionary processes underlying the high sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse. By analyzing 160 tumors from 65 patients using multiregion sequencing, the researchers found that treatment-naive SCLC exhibited clonal homogeneity at distinct tumor sites, while first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. Branched evolution and a shift to ancestral clones were observed, leading to tumor relapse. Effective radiotherapy or immunotherapy induced the re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. *TP53* and *RB1* alterations were exclusively part of the common ancestor, while *MYC* family amplifications were not always present in the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumors with clonal *CREBBP/EP300* alterations underwent genome duplications. Gene-damaging *TP53* alterations and co-alterations of *TP73*, *CREBBP/EP300*, or *FMN2* were significantly associated with shorter disease relapse following chemotherapy. The study highlights the importance of the common ancestor in driving clonal diversity at relapse and identifies key genomic patterns associated with sensitivity and resistance to chemotherapy.