Parkinson disease (PD) is a progressive neurodegenerative condition characterised by tremor, bradykinesia and rigidity, as well as other motor and non-motor symptoms, for which no effective disease-modifying treatments have been discovered. Neuroprotection in PD is limited by its clinical and biological heterogeneity, suboptimal preclinical models, lack of established disease progression biomarkers, complex pathophysiology, the existence of effective symptomatic therapies which hamper the detection of actual disease modification, and trial design. This review discusses the above issues and other important concepts in neuroprotection in PD. The main pathophysiological mechanisms in PD are classified into mitochondrial dysfunction, lysosomal dysfunction, inflammation, protein aggregation/propagation, and "other", and discussed briefly. The most relevant disease-modifying candidates in PD are classified into the aforementioned categories and reviewed. Finally, conclusions and recommendations for future improvements in the field of disease modification in PD are provided.