The subjective experience of one’s environment is constructed by interactions among sensory, cognitive, and affective processes. For centuries, meditation has been thought to influence such processes by enabling a non-evaluative representation of sensory events. To better understand how meditation influences the sensory experience, we examined brain activity by which meditation influences pain. After four-days (20m/d) of mindfulness-based mental training, meditation during noxious stimulation significantly reduced pain-unpleasantness by 57% and pain-intensity ratings by 40% when compared to non-meditation. Functional brain imaging revealed that meditation modulates pain via multiple mechanisms characterized by a reduction of pain-related activity in the primary somatosensory cortex, attenuation of pain-intensity in the anterior cingulate and anterior insula, and regulation of affective responses in the orbito-frontal cortex and thalamus. These data suggest that meditation reframes the contextual evaluation of sensory events and provide a novel perspective into the brain mechanisms involved in meditation and meditation-related pain relief.