Chronic L-dopa therapy is associated with the development of motor complications in the majority of Parkinson's disease (PD) patients. Although the precise mechanism responsible for these events is not known, increasing laboratory and clinical evidence points to a sequence of events that is initiated by abnormal pulsatile stimulation of dopamine receptors by the intermittent administration of agents with short half-lives such as L-dopa. Initiating therapy with a long-acting dopamine agonist has been shown to delay the onset and reduce the severity of motor complications in MPTP monkeys and PD patients. Administering L-dopa with a catechol-O-methyltransferase (COMT) inhibitor to block its peripheral metabolism increases its plasma half-life and might have a similar effect. Thus, a rational strategy for treating PD would be to initiate therapy with a long-acting dopamine-receptor agonist and supplement at the appropriate time with L-dopa combined with a COMT inhibitor.