Our ability to conduct whole organism toxicity tests to understand chemical safety has been outpaced by our ability to synthesize new chemicals for a wide variety of commercial applications. Therefore, to increase efficiencies in chemical risk assessment, scientists and risk assessors are turning to mechanistic-based studies, making greater use of in vitro and in silico methods, to evaluate potential environmental and human health hazards. A framework that has gained traction for capturing available knowledge describing the linkage between mechanistic data and the apical toxicity endpoints, required for regulatory assessments, is the adverse outcome pathway (AOP). A number of international activities have focused on AOP development and plausible applications to regulatory decision-making. These interactions have prompted dialog between research scientists and regulatory communities to consider how best to use the AOP framework in risk assessment. While expert-facilitated discussions have been instrumental in moving the science of AOPs forward, it was recognized that a survey of the broader scientific community would aid in identifying current limitations while guiding future initiatives for the AOP framework. To that end, a global ‘Horizon Scanning’ exercise was conducted to solicit questions concerning the challenges or limitations that must be addressed to realize the full potential of the AOP framework in research and regulatory decision making. The majority of questions received fell into several broad topical areas including the concepts of AOP networks and quantitative AOPs, collaboration on and communication of AOP knowledge, AOP discovery and development, chemical and cross-species extrapolation, exposure considerations, and AOP applications. An expert ranking exercise was then conducted to identify the most important questions for each category. These questions were used to develop four broad themes to inform and guide future AOP research and regulatory initiatives. In addition, frequently asked questions (FAQs) were identified and addressed by experts in the field. Answers to FAQs will aid in framing further discussions about common misperceptions about AOPs and allow for clarification of AOP topics. The need for clarification occurred with surprising frequency, indicating that improvements are needed in communicating the AOP framework among the scientific and regulatory communities. Overall, the ‘Horizon Scanning’ effort brought together the global scientific community to guide the direction of future initiatives and identify key questions surrounding the AOP framework. The views expressed in this manuscript are those of the authors and may not reflect U.S. EPA policy. This dataset is not publicly accessible because: It is available online and was collected through the Society of Environmental Toxicology and Chemistry in support of a Pellston Workshop. It can be accessed through the following means: All materials associated with this paper are found at the provided URL as the main document or as the supplemental files. Format: http://onlinelibrary.wiley.com/doi/10.1002/etc.3805/full. This dataset is associated with the following publication: LaLone, C., G. Ankley, S. Belanger, M. Embry, G. Hodges, D. Knapen, S. Munn, E. Perkins, M. Rudd, D. Villeneuve, M. Whelan, C. Willett, X. Zhang, and M. Hecker. Advancing the adverse outcome pathway framework - An international horizon scanning approach. SOCIETY OF ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY JOURNAL. Society of Environmental Toxicology and Chemistry, Pensacola, FL, USA, 36(6): 1411-1421, (2017).