Nature Reviews Drug Discovery, Published online: 13 July 2026; doi:10.1038/s41573-026-01481-9 Simulation-guided clinical trial design can enable identification of the optimal design to bring safe and effective therapies to patients as efficiently as possible, and it is particularly useful when exploring innovative strategies such as adaptive designs and master protocols. This Perspective discusses the value of trial simulations from the perspective of different stakeholders involved in drug development, presents best-practice recommendations, and highlights case studies that illustrate the impact of the approach.