Despite a preponderance of evidence suggesting an organic rather than psychogenic origin for Tourette syndrome, the precise neurobiological abnormality remains speculative. Neuroanatomically, there is expanding confirmation that cortico-striato-thalamo-cortical pathways represent the site of origin for tics and accompanying neuropsychiatric problems. Pathophysiological hypothesis are generally defined based on involvement of (1) a specific anatomical site (striato-thalamic circuits, striatal compartments), (2) physiologic abnormality (excess thalamic excitation, impaired intracortical inhibition), or (3) involvement of a specific neurotransmitter or synaptic component. This review provides information essential for understanding current and future proposals pertaining to the neurobiology of this intriguing disorder.