Parkinson\'s disease is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons. Current treatment is focused on mitigating the symptoms through the administration of levodopa, rather than on preventing dopaminergic neuronal damage. Therefore, the use and development of neuroprotective/disease-modifying strategies is an absolute need that can lead to promising gains on translational research of Parkinson\'s disease. For instance, N-acetylcysteine, a natural compound with strong antioxidant effects, has been shown to modulate oxidative stress, preventing dopamine-induced cell death. Despite the evidence of neuroprotective and modulatory effects of this drug, as far as we know, it does not induce per se any regenerative process. Therefore, it would be of interest to combine the latter with innovative therapies that induce dopaminergic neurons repair or even differentiation, as stem cell-based strategies. Stem cells secretome has been proposed as a promising therapeutic approach for Parkinson\'s disease, given its ability to modulate cell viability/ preservation of dopaminergic neurons. Such approach represents a shift in the paradigm, showing that cell-transplantation free therapies based on the use of stem cells secretome may represent a potential alternative for regenerative medicine of Parkinson\'s disease. Thus, in this review, we address the current understanding of the potential combination of stem cell free-based strategies and neuroprotective/disease-modifying strategies as a new paradigm for the treatment of central nervous system neurodegenerative diseases, like Parkinson\'s disease.