The possibility of engineering mice genetically over four decades ago heralded a transformative era in scientific inquiry, including in the cancer research field. Since then, continuous refinements and innovations have propelled the creation of experimentally controllable, genetically precise animal models for an array of human cancers. Recent strides in genome editing technologies have further accelerated the pace of advancement in this domain, serving as a catalyst for reshaping the trajectory of precision medicine for patients with cancer. With the new ability to manipulate genes more rapidly and with a higher throughput, researchers in the field can now delve into intricate but fundamental details of cancer biology. The crux of these technological advancements lies in their capacity to facilitate the functional evaluation of an unprecedented number of alterations found in human tumors. This, in turn, has given rise to pre-clinical and co-clinical platforms that provide invaluable insights into the efficacy of novel therapeutic interventions. These platforms extend beyond mere assessments, allowing for a nuanced exploration of the intricate mechanisms underlying therapeutic resistance—a critical frontier in contemporary cancer research.