Novelty detection is a fundamental capacity of all mammalian nervous systems /64/. The ability to orient to unexpected events is critical for both survival and normal memory function /82/. The mechanisms whereby the brain detects and responds to novelty have become of increasing interest to neuroscientists. A review is provided of human electrophysiological and blood flow data focused on delineating the neural systems engaged by novelty. Electrophysiological recording of event-related potentials (ERPs) has shown that novel stimuli activate a distributed network involving prefrontal and posterior association cortex as well as the hippocampus /4,23,24,32,33,36,86,88/. Activation of this network facilitates subsequent memory for novel events /27/. Neural modeling provides additional support for a prominent role of novelty in normal memory function /43/. Blood flow studies employing PET and fMRI have also begun to define the neural regions activated by novelty. The blood flow data provide converging evidence on the role of the hippocampus and cortical association regions in the processing of novelty /30,66,75,76/. The results of the behavioral, ERP and blood flow research confirm that a distributed neocortical-limbic circuit is activated by stimulus novelty. These distributed circuits maintain a template of the recent past /74/. Deviations from the template activate a neocortical-limbic network facilitating behavioral response to and memory storage of novel events.