More than 50% of all patients with Parkinson's disease who initially receive treatment with conventional levodopa will develop late complications, although the underlying mechanisms are not completely understood. Some aspects of levodopa peripheral pharmacokinetic handling contribute to response fluctuations, such as its short half-life and the variations of gastrointestinal absorption and blood-brain barrier transport caused by competition with neutral amino acids. In themselves, however, these are insufficient to explain the late occurrence of “on-off” oscillations. Disease-related central changes in presynaptic handling of levodopa are likely to play a role, as are postsynaptic pharmacodynamic receptor changes, possibly induced by chronic, nonphysiologic, pulsatile stimulation. Pharmacodynamic alterations of dopaminergic receptors have also been implicated in the pathogenesis of levodopa-induced dyskinesias. Recent experimental findings suggest a possible role of downstream functional changes in pallidosubthalamo-thalamic projections.