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Parkinson’s disease (PD), like other neurodegenerative diseases, lacks a disease-modifying therapy. While we have solutions to counteract the dopaminergic depletion that ensues at the level of the striatum following the progressive loss of substantia nigra neurons in the midbrain, and therefore, are capable of reversing the motor symptoms experienced by patients, our understanding of the molecular mechanisms that trigger degeneration is minimal. Even following the discovery of single mutations in several genes that can cause familial forms of PD, like PINK1 and PRKN, we are still deprived of a deep appreciation of the basic biological mechanisms that drive disease initiation and progression. In Chapter 1 of this thesis, I describe the remarkable research progress that was made in the last two centuries following the original description of the disease. I detail how the mitochondrial hypothesis of PD emerged from brilliant discoveries, the advent of new biochemical and genomic tools, and even a few accidents, and how it may underlie the selective vulnerability of midbrain dopamine neurons that die in PD. Finally, I introduce some key unanswered questions in the field of PD research that I begin to address in this thesis. In Chapter 2, I describe the novel approach we developed to study a pathway of mitochondrial turnover that is critical in PD, which allowed us to track individual mitochondria at every step of the degradation process in neurons. We gained unprecedented insight into the fate of these mitochondria once they reach the lysosomal compartment which led to us to identify new steps of PINK1/PRKN-mediated mitochondrial degradation. These findings may have important implications for both basic biology and disease pathophysiology. In Chapter 3, I describe a mouse model we developed to assess the impact that chronic changes in neural activity have on the function and survival of midbrain dopamine neurons. We find that the substantia nigra dopamine neurons are preferentially vulnerable to chronic increases in neural activity, while other dopamine neurons are more resilient, suggesting a potential role for chronic hyperactivity as a driver of disease. Lastly, in Chapter 4, I elaborate and speculate on disease implications of the findings described in Chapter 2. I contextualize our contribution within the broader effort to understand why PINK1 and PRKN are so crucial to neurons under certain high-stress conditions, but are dispensable at baseline.