The specific loss of substantia nigra compacta (SNc) neurons in Parkinson's disease (PD) has been the main driving force in initiating research efforts to unravel the apparent SNc-specific vulnerability. Initially, metabolic constraints due to high dopamine turnover have been the main focus in the attempts to solve this issue. Recently, it has become clear that fundamental differences in the molecular signature are adding to the neuronal vulnerability and provide specific molecular dependencies. Here, the different processes that define the molecular background of SNc vulnerability are summarized.