Abstract When metastatic cancers are challenged with targeted agents, almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near certainty of disease recurrence following treatment with targeted agents? Addressing this question means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumors’ evolution, the emergence of drug resistance can be controlled. We find that clonal dynamics can be monitored in real time in the blood of patients, and liquid biopsies can be used to intercept the emergence of resistant clones before relapses are clinically manifest. We discovered that a multistep clonal evolution process driven by progressive increases in drug fitness underlies the development of resistance in cells and patient avatars. To have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. One possibility is to anticipate the changes the tumors will make. For example, by knowing in advance how CRC cells overcome resistance to EGFR blockade, we devised further rounds of therapy. These findings became the bases of clinical trials aimed at targeting cancer evolution and exploiting liquid biopsies to monitor the emergence of drug resistance and to design further lines of therapies. Citation Format: Alberto Bardelli. Tracking and targeting colorectal cancer evolution [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA13.