Integrating mindfulness-based practices with a harm reduction approach can be particularly useful in the treatment of substance misuse and co-occurring disorders. This chapter focuses on the theory and application of mindfulness practices to address substance use and other risky behaviors from a harm reduction perspective (Bowen et al. 2010). Conceptualizing substance misuse as stemming from the complex interaction of biopsychosocial factors that leads one to self-medicate requires that we adopt a highly individualized approach that is attuned to the goals and needs of each person (Murphy and Khantzian in Psychotherapy and substance abuse. Guilford, New York, 1995; Tatarsky in Harm reduction psychotherapy. Rowman & Littlefield Publishers, Inc, Lanham, 2007). Mindfulness practices are uniquely suited to helping people across the spectrum of substance use issues as it provides a framework observing one’s experiences with curiosity and kindness and enhances the development of self-regulation capacities. Working from a harm reduction approach, with its emphasis on collaboration and empowerment helps clients explore the types of changes they wish to make and supports them in attaining their goals. Clinical examples and a case discussion are provided to illustrate this integrative approach.