Patients with early Parkinson’s disease (PD) characteristically experience a remarkable benefit from levodopa. Restoration of dopaminergic transmission with the dopamine precursor can suppress parkinsonian symptoms to the point in which, unlike with any other neurodegenerative disorder, some patients can feel essentially “back to normal.” Unfortunately, this situation is not ever-lasting1; the combination of disease progression and levodopa therapy increasingly compromises the favorable response to levodopa in several ways. 2 Of these, fluctuations of the “wearing-off” and “on–off” types and peak-dose dyskinesias are the most common. 3 The disability associated with these motor response complications (MRCs) rivals that caused by the disease itself. MRCs are hardly unique to levodopa therapy, but also occur with relatively short-acting dopamine agonists when given at fully effective doses. 4, 5 A highly effective, rationale-based therapy, such as levodopa for PD, is without precedent in the field of neurodegenerative disorders. Perhaps that fact has been the major driving force behind the exploration of the pathogenetic mechanisms underlying MRCs: clearly, if MRCs could be prevented, treatment of PD would be tremendously improved. Three major questions to be answered are: Why does the response to levodopa change over time? Where in the brain does this change occur? What are the mechanisms involved? Many answers to these questions remain unproven, but collective results of preclinical and clinical research over the last decade at least suggest viable hypotheses that are presently being tested.