The subjective experience of pain is truly unique since the percept of a noxious stimulus can vary greatly depending on the context in which the sensory event takes place. Even within the same context, different internal cognitive information related to previous experience, affective state, and attention unique to each individual may importantly influence how a nociceptive stimulus will be experienced. Although attempts have been made to elucidate the mechanisms by which cognitive information influences the pain processing, most studies describe these influences in terms of the facilitation and attenuation of incoming sensory nociceptive information via descending pain control systems. However, multiple lines of evidence suggest that neural mechanisms operating at supraspinal level may allow cognitive information to directly influence cortical processing of nociceptive information. In contrast to studies that show attenuation or facilitation of incoming sensory information from the spinal cord, these supraspinal neural mechanisms may directly influence how nociceptive information is processed at the cortical level. In the present investigations, we show clear data to provide useful insights into the neural mechanisms that can support cognitive influences on supraspinal nociceptive processing. We found that a large portion of interindividual variations in pain sensitivity can be accounted for by variations in various psychological factors that are processed at the supraspinal level. Furthermore, the neural circuitries associated with the insula and the putamen can, via different routes of action, utilize various cognitive and contextual information unique to each individual from brain areas involved in memory, attention, and affect to influence cortical processing of nociceptive information. Specifically, these mechanisms may involve the direct modulation of various nociceptive processing brain areas as well as the selection of appropriate cortical networks to process the incoming nociceptive information in a context-relevant manner. The proposed neural mechanisms allow the organism to appropriately respond and attend to the stimuli that are more behaviorally relevant while avoiding unnecessary alarm response to noxious stimuli that are of less potential danger. Accordingly, these dynamic interactions may be important in shaping a complete subjective experience of pain and may contribute to the large interindividual differences in pain experience.