Levodopa is still recognised to be the “gold standard” symptomatic treatment for Parkinson’s disease. After 4–5 years however, its clinical efficacy declines and patients may experience the so-called “long-term levodopa syndrome”, which represents the clinical counterpart of the changes of pharmacodynamic response to the drug. Long duration response (LDR) is substituted by the short duration response (SDR), which is responsible for the fluctuations of the clinical response. Strategies aimed at maintaining the clinical benefits for as long as possible and postponing the occurrence of motor complications as late as possible have been at the centre of scientific debates in recent years. We are still far from optimal use of the drug in the different stages or the disease, both regarding mode of administration and dose adjustment to individual needs.