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Interest in mindfulness as a tool to improve health and well-being has increased rapidly over the past two decades. Limited qualitative research has been conducted on mindfulness and health. This study utilized in-depth interviews to explore the context, perceptions, and experiences of a sub-set of participants engaged in an acceptability study of mindfulness-based stress reduction (MBSR) among urban youth. Content analysis revealed that all in-depth interview participants reported experiencing some form of positive benefit and enhanced self-awareness as a result of MBSR program participation. Significant variation in the types and intensity of changes occurring was identified, ranging from a reframing and reduction of daily stressors to transformational shifts in life orientation and well-being. Variations in perceptions of and experiences with mindfulness should be studied in further depth in the context of prospective intervention research, including their potentially differential influence on mental and physical health outcomes.