Mindfulness involves nonjudgmental attention to present-moment experience. In its therapeutic forms, mindfulness interventions promote increased tolerance of negative affect and improved well-being. However, the neural mechanisms underlying mindful mood regulation are poorly understood. Mindfulness training appears to enhance focused attention, supported by the anterior cingulate cortex and the lateral prefrontal cortex (PFC). In emotion regulation, these PFC changes promote the stable recruitment of a nonconceptual sensory pathway, an alternative to conventional attempts to cognitively reappraise negative emotion. In neural terms, the transition to nonconceptual awareness involves reducing evaluative processing, supported by midline structures of the PFC. Instead, attentional resources are directed toward a limbic pathway for present-moment sensory awareness, involving the thalamus, insula, and primary sensory regions. In patients with affective disorders, mindfulness training provides an alternative to cognitive efforts to control negative emotion, instead directing attention toward the transitory nature of momentary experience. Limiting cognitive elaboration in favour of momentary awareness appears to reduce automatic negative self-evaluation, increase tolerance for negative affect and pain, and help to engender self-compassion and empathy in people with chronic dysphoria.