This chapter discusses US FDA’s Project Optimus and its profound impact on contemporary oncology drug development. Since its debut in 2021, this groundbreaking initiative had fundamentally changed the oncology dose-finding paradigm: discouraging outdated conventions since the era of cytotoxic agents (identifying the maximum tolerated dose, MTD), and embracing new practices of identifying the optimal dosage among multiple doses based on totality of data preferably in a randomized setting. We outline a chronicle of milestones for this initiative in the past three years, with an in-depth discussion of the sotorasib development journey to understand the background and motivation behind Project Optimus. We elucidate why earlier methodologies and designs centered on the MTD or optimal biological dose (OBD) may be inadequate to meet the expectations of Project Optimus, and introduce a selection of novel approaches recently developed that follow the guiding principles of the initiative, some of which had been accepted by the Agency for implementation in real trials. Some regulatory perspectives with suggested analyses in the optimization data package and practical considerations related to optimizing dose in combination studies, pediatric studies, master protocols, and particular diseases are also discussed. Some predictions of future practices are made to conclude this chapter.