Global Challenges are becoming ever more central to the EU’s foreign policy objectives. The EU’s New Global Strategy (2019-2024) states that, “The EU will use its influence to lead the response to global challenges.” We ask in this paper: How? What gives the EU the capacity to act regarding global challenges? On what basis does the EU’s influence and potential for leadership rest? The Europe-as-a-power debates identify two main sources from which European power is derived: one, the single market (the Market Power Europe approach), and two, the attractiveness of Europe’s norms and values (the Normative Power Europe approach). In this paper, we show that both approaches are lacking when it comes to explaining how the EU has engaged with global challenges to exert leadership and influence on a global level. Building on our previous research showing that knowledge is a missing element in European foreign policy discourses, we look specifically at climate change and food security to see how knowledge is mobilized as power within global challenges. The climate change case is a most-likely scenario, where the EU has taken a leadership role, whereas the food security case is an example where the science is still fraught and the policy approach divided between the EU, US, China and Brazil. These contrasting cases, drawing on data collected in the Horizon 2020 project S4D4C (Using Science Diplomacy for Addressing Global Challenges), provide insight into the mechanisms, practices and interests involved in the EU’s attempts to develop its foreign policy through the knowledge-intensive global governance objects of climate change and food security.