Patients with Parkinson's disease generally have a smooth clinical response from levodopa therapy for the first 3 to 5 years. Motor fluctuations later become noticeable and may ultimately give way to unpredictable responses to treatment. Mechanisms responsible for motor fluctuations are not fully understood, but can be separated into three groups: (1) central pharmacokinetics, or delivery of dopamine from the presynaptic to the postsynaptic receptor; (2) peripheral pharmacokinetics, or delivery of levodopa from an exogenous source to the brain; and (3) pharmacodynamics, or alterations in the interactions between dopamine and the striatal receptor. Changes in central pharmacokinetics caused by diminished presynaptic dopamine storage capacity probably account for early end-of-dose "wearing-off." As patients lose further storage capacity, peripheral levodopa pharmacokinetics may play an important role in the fluctuation response from erratic gastric emptying or variables that change gut-to-blood and blood-brain barrier transport. Finally, erratic motor responses (eg, the "on-off" phenomenon) in advanced Parkinson's disease may be caused in part by alterations at the striatal dopamine receptor.