This study provides a comprehensive genomic analysis of small cell lung cancer (SCLC), a highly lethal form of lung cancer. The researchers sequenced the genomes of 110 SCLC tumors and identified several key biological processes and therapeutic targets. Key findings include: 1. **Universal Inactivation of *TP53* and *RB1***: Both *TP53* and *RB1* were found to be inactivated in almost all tumors, either through bi-allelic mutations or complex genomic rearrangements. This suggests that these tumor suppressors are obligatory in the development of SCLC. 2. **Oncogenic Genomic Events Affecting *TP73***: Recurrent genomic rearrangements were observed in *TP73*, leading to the creation of oncogenic variants such as p73Δex2/3. These variants have been shown to function as oncogenes in other cancers, suggesting potential therapeutic opportunities. 3. **Tumour Suppressive Roles of Notch in SCLC**: The study identified *NOTCH* family genes as tumor suppressors in SCLC. Inactivation of *NOTCH* signaling was found to inhibit tumor growth and extend survival in pre-clinical mouse models of SCLC. This suggests that Notch signaling may be a therapeutic target in SCLC. 4. **Novel Candidate Genes and Biological Processes**: The analysis uncovered several novel candidate genes and biological processes that may play a role in the pathogenesis of SCLC, providing potential targets for more effective targeted therapies. Overall, this comprehensive genomic analysis of SCLC identifies several key biological processes and therapeutic targets, offering new insights into the disease and potential treatment strategies.This study provides a comprehensive genomic analysis of small cell lung cancer (SCLC), a highly lethal form of lung cancer. The researchers sequenced the genomes of 110 SCLC tumors and identified several key biological processes and therapeutic targets. Key findings include: 1. **Universal Inactivation of *TP53* and *RB1***: Both *TP53* and *RB1* were found to be inactivated in almost all tumors, either through bi-allelic mutations or complex genomic rearrangements. This suggests that these tumor suppressors are obligatory in the development of SCLC. 2. **Oncogenic Genomic Events Affecting *TP73***: Recurrent genomic rearrangements were observed in *TP73*, leading to the creation of oncogenic variants such as p73Δex2/3. These variants have been shown to function as oncogenes in other cancers, suggesting potential therapeutic opportunities. 3. **Tumour Suppressive Roles of Notch in SCLC**: The study identified *NOTCH* family genes as tumor suppressors in SCLC. Inactivation of *NOTCH* signaling was found to inhibit tumor growth and extend survival in pre-clinical mouse models of SCLC. This suggests that Notch signaling may be a therapeutic target in SCLC. 4. **Novel Candidate Genes and Biological Processes**: The analysis uncovered several novel candidate genes and biological processes that may play a role in the pathogenesis of SCLC, providing potential targets for more effective targeted therapies. Overall, this comprehensive genomic analysis of SCLC identifies several key biological processes and therapeutic targets, offering new insights into the disease and potential treatment strategies.