The United State is at a pivotal time in efforts to improve the health, education, and well-being of children, youth, and families. There is increasing recognition that population-level results cannot be achieved without closing persistent equity gaps--gaps defined by race, class, income, ethnicity, immigration status, gender, and urban/rural geography. The encouraging news is that leaders in philanthropy, in government, and within many communities are implementing strategies to address health disparities, reduce poverty and boost incomes, create effective schools, and transform tough neighborhoods--all to achieve better, more equitable outcomes. These complex initiatives usually involve transforming public systems or revitalizing communities or both. To promote an equitable approach to generating and using knowledge, the authors believe three essential elements must be included in the knowledge development enterprise: (1) Valuing and using the perspectives and knowledge of people most affected by the root causes of inequity and by the proposed solutions; (2) Understanding and articulating the structural, systemic, cultural, and historical factors that are root causes of inequities; and (3) Focusing on the variations in impact of interventions--not just "what works" on average, for some individuals, somewhere--to discern what adaptations are needed to reduce disparities. In this paper, the authors turn their attention to considering these elements in light of what it means to "place equity concerns at the center" of improving outcomes for those who are the most marginalized. The premise is that how evidence is generated and applied--i.e., the assumptions made and methods chosen for this task--can affect how rapidly people learn and how effectively they'll make progress in achieving more equitable outcomes.