OBJECTIVE: It has been nearly 15 years since Kazdin and Nock published methodological and research recommendations for understanding mechanisms of change in child and adolescent therapy. Their arguments and enthusiasm for research on mechanisms of behavior change (MOBCs) resonated across disciplines and disorders, as it shined a light on the crucial importance of understanding how and for whom treatments instigate behavior change and how therapeutic mechanisms might be extended to "situations and settings of everyday life." Initial efforts focused on how psychotherapy works and linear models, yet the use of theory to guide the study of mechanisms, and laboratory experiments to manipulate them, is broadly applicable. METHOD: This article considers dynamic physiological processes that support behavior change. Specifically, it examines the utility of psychophysiological methods to measure and promote behavior change. Moreover, it embeds the baroreflex mechanism, a well-defined heart-brain feedback loop, within the theories and strategies of MOBC research. RESULTS AND CONCLUSION: Individuals' subjective and expressive experience of change does not always align with their physiological reactivity. Thus, behavior change may be best understood when concurrently assessed across multiple biobehavioral levels. Further, behavior is initiated in the moment, often before conscious deliberation, suggesting that multilevel behavior change research may benefit from real-time methodological designs. Last, substance use trajectories vary widely, suggesting that different MOBCs are more or less active in individuals depending on their personal constituency and the functional need that their substance use serves; thus, methods that are amenable to personalized modeling approaches are important.