Studies on the concentration-effect relationship of levodopa in Parkinson's disease have established that: (1) in patients with a fluctuating response to levodopa, concentration-effect profiles are steeper and markedly shifted to the right (i.e. potency is decreased) compared with those patients whose symptoms are adequately controlled; (2) with controlled-release (CR) preparations, the concentration-effect relationship indicates a decreased potency compared with conventional immediate-release (IR) preparations; and (3) coadministration of a dopamine receptor agonist (even at a subclinical dose) enhances the potency of levodopa. These findings support some current hypotheses on the origin of, and the pathophysiological process underlying, response fluctuations. In patients with response fluctuations, metabolism of levodopa and storage of dopamine in the striatum are reduced. Levodopa is decarboxylated in the extracellular space, with the result that dopamine is released directly to the effect site. Thus, without dopamine storage acting as a buffer between levodopa metabolism and dopaminergic effect, the decline in motor response closely follows the decrease in levodopa concentrations. Even small fluctuations of levodopa concentrations around the EC50 value (the concentration threshold necessary to produce a motor response) might be followed by response fluctuations. Patients with Parkinson's disease who do not have response fluctuations exhibit a residual capacity of production and storage of endogenous dopamine; thus, lower amounts of 'exogenous' dopamine (formed by decarboxylation of levodopa) are required. The storage buffer is responsible for a time lag between decline in peripheral plasma concentrations of levodopa and dopamine-induced motor response. Low doses of a dopamine receptor agonist increase the basal tonus of the striatum, but do not reach the threshold concentration for triggering a motor response. Because of the dichotomic character of the motor response, patients do not switch from an 'off' (not responding) phase to an 'on' (responding) phase. However, lower amounts of exogenous dopamine released in the synaptic cleft will be necessary to induce response. To date, pharmacokinetic-pharmacodynamic modelling does not give a clear answer as to whether response fluctuations are additionally induced by receptor desensitisation or inhibition of the active transport of levodopa across the blood-brain barrier by the main metabolite of levodopa, 3-O-methyldopa. Nevertheless, there is some evidence that higher plasma concentrations of levodopa are required for similar motor effects when CR preparations are compared with IR preparations. Attempts have been made to establish therapeutic drug monitoring of levodopa in patients with response fluctuations. The interindividual variability of EC50 values in single studies is relatively low (10% to a maximum of 50%), which might allow specification of a 'population' threshold plasma concentration (i.e. a minimal effective plasma concentration required to obtain clinical effects). However, considering the short elimination half-life of levodopa, it seems doubtful whether such target drug concentrations can be maintained as steady-state. A marked prolongation of the dosage interval with CR preparations might be limited by the higher threshold concentrations of levodopa necessary to maintain clinical effects.