Many an academic health system (AHS) has grappled with the scale required to remain successful as markets consolidate and care migrates toward population-driven models. Determining “How many lives are needed?” is complex because it crosses different strategic and mission-related dimensions and should be driven by each system’s academic, clinical program and population health goals. Pursuing a course of action without first addressing what the AHS is seeking to achieve puts the organization at risk of not meeting or overshooting its targets. In this paper, we share a framework with real-life examples both academic and non-academic systems can use to define their goals for the number of lives needed to sustain their missions.