Parkinson's disease (PD) is primarily a sporadic condition which results mainly from the death of dopaminergic neurons in the substantia nigra. Its etiology remains enigmatic while its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. As of yet, most insights into PD pathogenesis are derived from toxic models of PD and show that the earlier cellular perturbations arising in dopaminergic neurons include oxidative stress and energy crisis. These alterations, rather than killing neurons, trigger subsequent death-related molecular pathways including elements of apoptosis. The fate of dopaminergic neurons in PD may also be influenced by additional factors such as excitotoxicity, emanating from the increased glutamatergic input from the subthalamic nucleus to the substantia nigra, and the glial response that arises in the striatum and the substantia nigra. In rare instances, PD can be familial, and those genetic forms have also provided clues to the pathogenesis of nigrostriatal dopaminergic neuron death including abnormalities in the mechanisms of protein folding and degradation as well as mitochondrial function. Although more remains to be elucidated about the pathogenic cascade in PD, the compilation of all of the aforementioned alterations starts to shed light on why and how nigral dopaminergic neurons may degenerate in this prominent disease, that is PD.