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Purpose: The purpose of this study is to create a methodological approach for identifying priority areas for science and technology (S&T) development and its empirical application within the city of Moscow. This research uncovers a wide range of multicultural and multidisciplinary global trends that will affect the development of major cities in an era of complexity and uncertainty, including the inherent complexity of urban contexts, demographic and socioeconomic trends, as well as scientific and ecological factors. Design/methodology/approach: The methodological approach is based on classic foresight instruments. Its novelty lays in the blending of qualitative and quantitative methods specially selected as the most appropriate for the identification of S&T areas in an era of complexity and uncertainty, including horizon scanning, bibliometric analysis, expert surveys and the construction of composite indexes with respect to the scope and resources of the research and the selected object for empirical application – Moscow, which is one of the world's largest megacities. The analysis was performed for the period of 2009–2018 and expert procedures took place in 2019. Findings: As a result, 25 global trends were identified, evaluated and discussed over the course of an expert survey and subsequent expert events. Ten priority areas of S&T development were determined, including 62 technological sub-areas within them and the most important market niches for all identified technological sub-areas, which could be useful for the world's megacities. The results of this study are illustrated using the construction sector. Based on the conducted research and results, a list of recommendations on S&T policy measures and instruments were suggested, including the creation of the Moscow Innovation Cluster, which by the end of 2023 contained more than 6,000 projects and initiatives, selected using the findings of this investigation. Originality/value: This research contributes to the existing literature and research agenda of setting priorities for S&T development and shows how it can be done for a megacity. The blended foresight methodology that was created within the study satisfies the criteria of scientific originality, is repeatable for any interested researcher, is applicable to any other city in the world and demonstrates its high efficiency in empirical application. It could be used for creating new agenda items in S&T policy, setting S&T priorities for a megacity and integrating the results into decision-making processes. This study provides recommendations on the further implementation of the designed methodology and results into a policymaking system. Moreover, the example of the Moscow Innovation Cluster, which was created based on the results of our research, demonstrates these recommendations' practical significance in real life, which is quite valuable. The limitation of this study is that it is not devoted to urban planning issues directly or the promotion of R&D areas; it is about setting promising S&T priorities in an era of complexity and uncertainty for megacities. [ABSTRACT FROM AUTHOR]