Many psychophysiologists have noted the striking similarities between the antecedent conditions for the P3 component of the event-related potential and the orienting response: both are typically elicited by salient, unexpected, novel, task-relevant, and other motivationally significant stimuli. Although the close coupling of the P3 and orienting response has been well documented, the neural basis and functional role of this relationship is still poorly understood. Here we propose that the simultaneous occurrence of the P3 and autonomic components of the orienting response reflects the co-activation of the locus coeruleus-norepinephrine system and the peripheral sympathetic nervous system by their common major afferent: the rostral ventrolateral medulla, a key sympathoexcitatory region. A comparison of the functional significance of the locus coeruleus-norepinephrine system and the peripheral sympathetic nervous system suggests that the P3 and orienting response reflect complementary cognitive and physical contributions to the mobilization for action following motivationally significant stimuli. Copyright © 2010 Society for Psychophysiological Research.