This article reviews the evolving field of radiobiology, emphasizing the need for advanced multiscale, mechanistic models to optimize radiopharmaceutical therapies (RPTs). While the traditional linear-quadratic model underpins external beam radiation therapy, RPT’s unique biological and spatial complexities demand new approaches. First-principles simulations of DNA damage, repair, and multicellular responses are crucial for understanding therapeutic efficacy and toxicity. The integration of these models into personalized, digital twin frameworks promises transformative clinical applications, but progress depends on deep mechanistic insights, experimental validation, and balancing model complexity with practicality for clinical use.