In the last half-century, Parkinson's disease (PD) has played a historical role in demonstrating our ability to translate preclinical scientific advances in pathology and pharmacology into highly effective clinical therapies. Yet, as highly efficacious symptomatic treatments were successfully developed and adopted in clinical practice, PD remained a progressive disease without a cure. In contrast with the success story of symptomatic therapies, the lack of translation of disease-modifying interventions effective in preclinical models into clinical success has continued to accumulate failures in the past two decades. The ability to stop, prevent or mitigate progression in PD remains the "holy grail" in PD science at the present time. The large number of high-quality disease modification clinical trials in the past two decades with its lessons learned, as well as the growing knowledge of PD molecular pathology should enable us to have a deeper understanding of the reasons for past failures and what we need to do to reach better outcomes. Periodic reviews and mini-reviews of the unsolved disease modification conundrum in PD are important, considering how this field is rapidly evolving along with our views and understanding of the possible explanations.