Potential neuroprotective therapies for Parkinson's disease (PD) are being identified in the laboratory and evaluated in the clinic in an effort to improve long-term outcomes for patients. Several clinical trial designs and methodologies have been used in an attempt to identify neuroprotective effects of medications. Such studies have evaluated (a) time to onset of a clinical milestone of disease progression, (b) progression of clinical symptoms from untreated baseline to an untreated endpoint obtained after wash-out of study intervention, (c) progression of clinical symptoms in early PD, (d) change in imaging markers over time, and (e) a combination of clinical (wash-out) and imaging markers. None of these approaches has yet provided a definitive means to evaluate neuroprotection. Clinical outcomes can be confounded by symptomatic effects of treatments, and imaging markers can be affected by pharmacologic or pharmodynamic changes resulting from treatment. Better methods of assessing putative neuroprotection in PD are needed.