The UN has increasingly become an organization focused on regional engagement. Better understanding and responding to risks at the regional level was a key priority for the 2017 reform initiated by Secretary-General Guterres and is also a clear priority in the 2021 Our Common Agenda. This emphasis on regional engagement is a response to the evolution of today’s risks, including the rise of transnational organized crime, globally-oriented violent extremist groups, large-scale population movements across borders, and the growing impacts of climate change. This project was guided by the question: How can the UN better integrate its regional prevention work to more effectively respond to major crises? This report provides a working definition of “prevention” and a brief overview of the evolution of regional prevention structures in the UN, and examines three regions where the UN has developed distinct regional approaches: the Sahel, the Horn of Africa, and Latin America. Drawing from these cases, and from an expert roundtable consultation with the UN offices in the Great Lakes, Central Africa, Western Asia and Headquarters, this report offers cross-cutting lessons and recommendations for the UN’s regional approaches going forward.