Intracranial recordings, lesion studies, and the combination of functional imaging with source analysis have produced a solid body of evidence about the generators of the P300 event-related potential. Although it is impossible to square all findings obtained across and within methodologies, a consistent pattern of generators has emerged, with target-related responses in the parietal cortex and the cingulate and novelty-related activations mainly in the inferior parietal and prefrontal regions. Stimulus modality-specific contributions come from the inferior temporal and superior parietal cortex for the visual and from the superior temporal cortex for the auditory modality. The P300 continues to be an important signature of cognitive processes such as attention and working memory and of its dysfunction in neurologic and mental disorders. It is increasingly being investigated as a potential genetic marker of mental disorders. Knowledge about the generators of the P300 will be crucial for a better understanding of its cognitive significance and its continuing clinical application.