Initiating and maintaining behavior change is key to the prevention and treatment of most preventable chronic medical and psychiatric illnesses. The cultivation of mindfulness, involving acceptance and nonjudgment of present-moment experience, often results in transformative health behavior change. Neural systems involved in motivation and learning have an important role to play. A theoretical model of mindfulness that integrates these mechanisms with the cognitive, emotional, and self-related processes commonly described, while applying an integrated model to health behavior change, is needed. This integrative review (1) defines mindfulness and describes the mindfulness-based intervention movement, (2) synthesizes the neuroscience of mindfulness and integrates motivation and learning mechanisms within a mindful self-regulation model for understanding the complex effects of mindfulness on behavior change, and (3) synthesizes current clinical research evaluating the effects of mindfulness-based interventions targeting health behaviors relevant to psychiatric care. The review provides insight into the limitations of current research and proposes potential mechanisms to be tested in future research and targeted in clinical practice to enhance the impact of mindfulness on behavior change.