The Adverse Outcome Pathway (AOP) framework provides a means to integrate radiobiological and epidemiological data across different levels of biological organisation for an adverse outcome of interest to regulatory decision-making. The AOP approach is envisioned to improve understanding of radiation-induced effects at low doses and dose-rates and decrease the uncertainty in radiation health risk assessment. To explore the challenges in the use of AOPs, an international horizon-style exercise (HSE) was initiated through the Nuclear Energy Agency (NEA) High-Level Group on Low Dose Research (HLG-LDR) Radiation/Chemical (Rad/Chem) AOP joint topical group. The HSE was completed in three phases. First, candidate research questions were solicited from radiation risk professionals via a dedicated website. Second, the over 250 questions submitted were refined by a dedicated steering committee using a best-worst scaling method. During a virtual 3-day workshop, the list of questions was further refined to the top 25 priority questions. Lastly, an internet-based survey of the broader radiation risk community lead to an orderly ranking of the 25 priority questions, again using a best-worst scaling method. Major themes from the survey included the ability of AOPs to address different levels of biological organisation, radiation quality, dose or dose rate, time patterns, and confounding variables. Broadly, these efforts will help advance the use of AOP in radiation research and regulation.