Behavior change is key to the prevention and treatment of most chronic medical illnesses and mental disorders. Cultivating mindfulness can result in transformative health behavior change. Yet, the mechanisms involved in the way mindfulness catalyzes and supports behavior change need to be elucidated. The Mindfulness Research Collaborative started to address this gap funded by the NIH Science of Behavior Change (SOBC) Initiative. Meta-analyses of randomized controlled trials (RCT) of MBCT and MBSR published before 2016 identified validated instruments representing promising mechanistic targets in 3 domains (cognitive [k=56], emotion regulation [k=72], self-related processes [k=16]). Following the SOBC process, we integrated the targets into two clinical trials of mindfulness-based interventions: one RCT focused on chronic illness self-management behavior change among primary care patients with anxiety, depression, and/or stress from chronic illness (MINDFUL-PC) (N=311), and the other focused on hypertension (MB-BP) (N=201). This symposium reviews the meta-analysis results and then presents the primary outcomes, mechanistic targets (e.g., interoceptive awareness, emotion regulation), neuroimaging, and mediation analyses from both SOBC-funded clinical trials. The panel will integrate clinical and neuroscience perspectives on the Mindful Self-Regulation model for behavior change.