Nature-based solutions (NbS) have emerged as a key strategy for sustainably addressing multiple urban challenges, with rapidly increasing knowledge production requiring synthesis to better understand whether and how NbS work in different social, ecological, economic, or governance contexts. Insights in this Perspective are drawn from a thematic review of 61 NbS review articles supported by an expert assessment of NbS knowledge in seven global regions to examine key challenges, fill gaps in Global South assessment, and provide insights for scaling up NbS for impact in cities. Eight NbS challenges emerged from our review of NbS reviews including conceptual, thematic, geographic, ecological, inclusivity, health, governance, and systems challenges. An additional expert assessment reviewing literature and cases in seven global regions further revealed the following: 1) Local context-based ecological knowledge is essential for NbS success; 2) Improved technical knowledge is required for planning and designing NbS; 3) NbS need to be included in all levels of planning and governance; 4) Putting justice and equity at the center of urban NbS approaches is critical, and 5) Inclusive and participatory governance processes will be key to long-term success of NbS. We synthesized findings from the NbS review results and regional expert assessments to offer four critical pathways for scaling up NbS: 1) foster new NbS research, technological innovation, and learning, 2) build a global NbS alliance for sharing knowledge, 3) ensure a systems approach to NbS planning and implementation, and 4) increase financing and political will for diverse NbS implementation.