Parkinson’s disease (PD) is a progressive neurodegenerative disease that affects millions of people around the world. PD is a neuropsychiatric disease characterized by both motor and non-motor symptoms.[1, 2, 3] The pathological hallmarks are the loss of dopaminergic neurons in the substantia nigra pars compacta, iron overload and alpha synuclein aggregates in the remaining dopaminergic cells.[4] By the time symptoms of PD appear, patients have lost 80 percent of their striatal or putaminal dopamine.[5] At present, there is no cure for PD; the available treatments are primarily symptomatic, and are essentially based on the restoration of dopaminergic transmission.[6] The concept of neuroprotection has been defined as the capacity to slow down, stop or reverse the course of the disease by protecting neurons against degeneration. Since there is no means of counting the number of remaining neurons in live patients, the concept of disease modification has been introduced. Although some encouraging preclinical data suggest that neuronal loss can be slowed, the clinical trial data have been largely disappointing.[7,8] Many factors could account for this failure (such as poorly understood disease mechanisms, and a medication’s pharmacokinetic and pharmacodynamics limitations) but some may be related to the choice of the clinical trial design. Another factor is the placebo effect observed in clinical studies; consequently, a large sample size is required.[9] Moreover, slow disease progression means that long-term, expensive studies are needed to detect a significant effect. Furthermore, it has already been pointed out that a drug’s symptomatic effect might mask a putative disease-modifying effect.[10,11] Lastly, the development of neuroprotective drugs is restricted by the lack of reliable biomarkers. In view of this lack of success, greater attention must be paid to selecting the most appropriate clinical trial design. This Viewpoint highlights adaptations of designs previously used in PD and also suggests the novel application of trial designs taken from outside the field of PD. Lastly, we make several recommendations for the assessment of disease-modifying drugs at each phase of clinical development.