Neuroimaging and neurophysiological studies have shown that transient nociceptive stimuli elicit responses in an extensive cortical network including somatosensory, insular and cingulate areas, as well as frontal and parietal areas. A long-standing view in the field of pain research has been that this network, often referred to as the “pain matrix”, represents the neural activity through which pain emerges as a percept. Recently, we have performed a number of studies challenging this interpretation. First, we conducted a number of experiments showing that pain intensity can be entirely dissociated from the magnitude of the responses in the so-called “pain matrix”, and that the magnitude of the elicited brain responses are strongly influenced by the context within which the stimulus appears, in particular, stimulus novelty. Second, using EEG and fMRI, we showed that non-nociceptive stimuli as well as stimuli not perceived as painful can elicit cortical responses having a spatial distribution that is indistinguishable from that of the “pain matrix”. For these different reasons, we proposed an alternative view of the functional significance of the “pain matrix”, in which it would reflect a system involved in detecting, orientation attention towards, and reacting to the occurrence of salient and/or behaviorally-relevant sensory events. Furthermore, we postulate that this cortical network might represent a basic mechanism through which significant events for the body’s integrity are detected, regardless of the sensory channel through which these events are conveyed.