The article explores the processes shaping the cancer genome and their impact on intratumor heterogeneity and drug development. It highlights the importance of understanding genome instability processes, such as mutational signatures, chromosomal instability, and whole-genome doublings, in shaping tumor evolution. The authors discuss the clinical implications of intratumor heterogeneity, including the challenges it poses for targeted therapies and the potential for polygenic drug resistance. They also explore future strategies, such as immune and adaptive approaches, to address these therapeutic challenges. The article emphasizes the need for longitudinal studies and advanced technologies to better understand tumor evolution and to develop more effective treatments.The article explores the processes shaping the cancer genome and their impact on intratumor heterogeneity and drug development. It highlights the importance of understanding genome instability processes, such as mutational signatures, chromosomal instability, and whole-genome doublings, in shaping tumor evolution. The authors discuss the clinical implications of intratumor heterogeneity, including the challenges it poses for targeted therapies and the potential for polygenic drug resistance. They also explore future strategies, such as immune and adaptive approaches, to address these therapeutic challenges. The article emphasizes the need for longitudinal studies and advanced technologies to better understand tumor evolution and to develop more effective treatments.