Efficacious translational research in health psychology relies on specifying why intervention strategies change health behaviors and when, for what behaviors, and for whom, do these strategies promote change. Whereas interventions' mechanism of action (the why question) has attracted considerable attention, there is a need to conceptualize and integrate factors that moderate intervention effectiveness. Intervention effects on health behaviors are a function of 2 change processes: how effectively interventions change mechanisms of action (target engagement), and how effectively those mechanisms change behavior (target validity). We outline the Operating Conditions Framework (OCF) to articulate theoretical linkages between mechanisms and moderators and begin the process of specifying circumstances that promote target engagement and target validity. A review of 46 meta-analyses of behavioral interventions offers impetus for the OCF by revealing that heterogeneity of effect sizes is frequent, substantial, and largely unexplained in traditional moderator analyses. We present an approach to moderation grounded on the distinction between 2 foci-engagement moderation and validity moderation-and reveal that little is known about variation in how interventions change targets and how changing targets promotes behavior change. The OCF addresses this need by maintaining researchers' focus on mechanisms of behavior change but doing so while embracing the conditional nature of these processes. Because the OCF prioritizes consideration of contextual factors at the outset of a research program, early-phase translational research will be critical in specifying operating conditions and, ultimately, generating guidelines regarding why, when, for whom, and for what behaviors are intervention strategies effective. (PsycInfo Database Record (c) 2022 APA, all rights reserved).