Developing and testing more effective health-related behavioral interventions is critical to making progress in improving disease prevention and treatment. One way to achieve this goal is to use a systematic and progressive framework that outlines the steps needed to translate theories, findings, and basic understandings about human behavior into risk factor and disease management or mitigation strategies. Although several frameworks and process models have been designed to inform the development and optimization of health-related behavioral interventions, little guidance is available to compare key aspects of these models, clarify their common and unique features, and aid in selecting the best approach for a specific research question. This article describes the major frameworks that focus on early phase translation-that is, approaches that address the design and optimization of behavioral interventions before testing in Phase III efficacy trials. Differences between and common features of these models are described, opportunities for combining frameworks to maximize their impact are noted, and guidance is provided to enable investigators to choose the most useful model(s) when designing and optimizing health-related behavioral interventions. The goal of this article is to promote the consistent use of frameworks that encourage a systematic, progressive approach to behavioral intervention development and testing as one way to encourage the creation of well-characterized, optimized, and potentially more effective health-related behavioral interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).