Governments and foundations around the world are urgently seeking strategies to optimize their investments across a range of distinctive missions targeted towards societal challenges. How should such investments be made, from early R&D spending to later-stage acceleration, to most effectively fuel the full lifecycle of innovation from ideas to impact? We answer this fundamental and urgent question by analyzing the boundary conditions of the most influential model of mission-driven innovation thus far, the much lauded Defense Advanced Research Project Agency (DARPA). We argue that the highly successful DARPA model is best suited to pursuing high-risk, high-reward research investment when applied to a targeted problem space that can be matched to a dense innovation ecosystem of potential solution providers. Such an environment allows for the identification and selection of the most promising avenues of research, from which extraordinary breakthroughs can emerge to address critical mission requirements. DARPA’s success therefore relies not only on the amount of funding available or the application of the agency’s specific system of complementary management practices, as has been the focus of prior analyses, but also on the nature of the innovation ecosystem to which it is being applied. Based on these insights, we develop the notion of four different Mission Arenas defined along two dimensions: the scope of the problem space and the density of potential solution providers within it, as a framework to understand when the DARPA model can be most usefully applied. We describe how some of these Mission Arenas can be actively managed towards a form more amenable for the DARPA model. We then focus on the Mission Arena that represents a nascent innovation ecosystem (e.g. an emerging research area where the scope of the problem is broad and solution providers are few) and argue for an entirely different approach to high-risk, highreward research investment altogether. We introduce the Ecosystem Growth Model, which transforms the DARPA model from one focused on strategic selection to one focused on strategic growth instead, by emphasizing program iteration, solution provider incentivization, portfolio integration, and organizational bandwidth.