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Consensus could be reached that there is overwhelming evidence of preclinical neuroprotection. However, the evidence of neuroprotection/neurorescue under clinical conditions is limited. Lessons from clinical trials designed to show neuroprotection (selegiline, amantadine, dopamine agonists) demonstrate that with the drugs available neuroprotection/neurorescue has to start as early as possible. A PET-controlled clinical trial with ropinirole shows that there seems to be a good chance for neuroprotection in the early phase of Parkinson's disease in patients treated from the very beginning of the disease while there is no such benefit in patients with a late start of a neuroprotective therapeutic strategy. Also long-term clinical neuroprotection cannot be reached. Complicating factors to demonstrate clinical neuroprotection are discussed.