Parkinson disease is an age-related neurodegenerative disease that affects approximately 1 million persons in the United States. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but most patients develop motor complications with long-term treatment, and features develop such as postural instability, falling, and dementia that are not adequately controlled with existing medications. Accordingly, neuroprotective therapy that might slow, stop, or reverse disease progression is urgently needed. While many agents appear to be promising based on laboratory studies, selecting clinical end points for clinical trials that are not confounded by symptomatic effects of the study intervention has been difficult. More recently, neuroimaging end points have been used as biomarkers of disease progression, but again there are concerns that they may be influenced by regulatory effects of the drugs used. We review clinical trials aimed at detecting neuroprotection in Parkinson disease and address the controversies surrounding the interpretation of these studies.