<p>Recent biological frameworks of Parkinson’s disease (PD) rely on the new advances in α-synuclein detection in biological tissues, mostly through α-synuclein seed amplification assays, and are mainly aimed at intercepting pre-clinical or early phases of disease to be subjected to disease-modifying therapies targeting α-synuclein. However, α-synuclein pathology alone is insufficient to explain the observed clinical heterogeneity of PD. Indeed, it has been demonstrated that a number of additional elements, such as genetics, comorbidities, co-pathology, and environmental factors, may influence PD phenotype and progression. Such factors have been partially accounted for or completely overlooked by both biological frameworks and would instead represent features which could explain, at least partially, the clinical and pathophysiologic diversities of PD and further represent potential druggable targets. Recognizing that the clinical heterogeneity of PD is a window to understand the pathophysiologic complexity of the disease might turn useful for a refinement of the current biological frameworks and move the field to satisfy the unmet need of establishing a precision medicine framework for this prevalent disorder.</p>