Despite advances in understanding the pathogenesis of Parkinson’s disease (PD), treatments that favorably influence the course of illness have remained elusive. In order to identify potentially neuroprotective interventions, improved clinical trial designs are needed. Researchers have to carefully consider what type of PD patients, how to measure the impact of putative neuroprotective agents, how to choose which interventions to study and what sequence of clinical trial designs is most appropriate. The possible use of futility studies to rapidly identify strongly ineffective agents and the use of delayed start designs to identify disease modifying interventions may both be important advances. Improved clinical trial design along with continued new insights into PD pathogenesis will likely lead to the identification of agents which can favorably influence the course of this disease.