Developmental relationships are characterized by reciprocal human interactions that embody an enduring emotional attachment, progressively more complex patterns of joint activity, and a balance of power that gradually shifts from the developed person in favor of the developing person. The working hypothesis of this article is that developmental relationships constitute the active ingredient of effective interventions serving at-risk children and youth across settings. In the absence of developmental relationships, other intervention elements yield diminished or minimal returns. Scaled-up programs and policies serving children and youth often fall short of their potential impact when their designs or implementation drift toward manipulating other “inactive” ingredients (e.g., incentive, accountability, curricula) instead of directly promoting developmental relationships. Using empirical studies as case examples, this study demonstrates that the presence or absence of developmental relationships distinguishes effective and ineffective interventions for diverse populations across developmental settings. The conclusion is that developmental relationships are the foundational metric with which to judge the quality and forecast the impact of interventions for at-risk children and youth. It is both critical and possible to give foremost considerations to whether program, practice, and policy decisions promote or hinder developmental relationships among those who are served and those who serve.