In the United States, advances in cancer treatment over the past two decades have contributed to rapid declines in mortality for multiple cancers, including leukemia 2023, kidney cancer, and melanoma (Siegel, CA Cancer J Clin 73(1):17–48, 2023). The development of targeted therapies, in particular, has dramatically altered the therapeutic landscape and improved outcomes for patients. Despite the seismic changes that have occurred in the field, some aspects of oncology drug development, notably dose-finding, have remained relatively static. In recent years, growing recognition of the crucial nature of dose optimization for oncology drugs within the clinical and regulatory communities has drawn increased attention to this issue. With the launch of Project Optimus in 2021 and the issuance of draft guidance for industry in 2023, the US Food and Drug Administration (FDA) has signaled its intention to prioritize optimizing the dosage of oncology drugs in the pre-approval setting, marking a shift away from the standard practice (FDA, Project Optimus. Available via https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus . Cited 18 Nov 2023, 2023a; Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases. Guidance for Industry. Available via https://www.fda.gov/media/164555/download . Cited 18 Nov 2023, 2023b). In this chapter, the historical practice of dose selection and its limitations are reviewed, and new regulatory guidance and proposed alternative approaches are explored.