There has been significant progress in our knowledge of the cause, the pathogenesis, and the nature of the mechanism of cell death in Parkinson's disease (PD). Mutations in single genes have now been shown to be able to cause PD but likely only account for a small number of cases. Alternatively, there is evidence that environmental factors play a large role in the majority of cases of sporadic PD. Most likely, genetic factors predispose patients to develop PD if combined with other gene mutations or environmental toxins. Interest has thus focused on factors that contribute to the pathogenesis of neurodegeneration and the mechanism of cell death in an attempt to design a neuroprotective therapy. Oxidant stress, mitochondrial dysfunction, excitotoxicity with excess nitric oxide formation, and glia and inflammatory processes are all thought to contribute to the cell death process and agents that interfere with these events may be neuroprotective. It is now generally held that the final culmination of these events is the induction of apoptosis in nigral dopaminergic neurons and this too offers opportunities for providing neuroprotection. A rational argument can be made for investigating a large number of different approaches or combination of approaches in the hope of developing a meaningful neuroprotective therapy, using clinically relevant indices and neuroimaging markers of nigral dopaminergic neurons. It is evident that conventional approaches to trials that utilize large numbers of patients in search of small incremental effects are costly and time consuming. As such, it will be virtually impossible to test all of the potentially valuable neuroprotective agents that are now at hand, let alone those that will likely soon emerge. We suggest that it may be more profitable to test a large number of agents in a small number of selected patients in search of a more robust neuroprotective effect. In this way, we will reduce the risk of missing a powerful neuroprotective treatment with a treatment that might not otherwise have been studied because of a lack of time, money, or patients.