Significance: Activation of mitochondrion-dependent programmed cell death (PCD) pathways is instrumental to the demise of substantia nigra pars compacta dopaminergic neurons in experimental mouse models of Parkinson's disease (PD). Supporting the relevance of these findings for PD, key molecular elements of this pathogenic cascade have also been demonstrated in postmortem brain samples of PD patients. Recent Advances and Critical Issues: Mounting evidence indicates that different morphological types of cell death co-exist in the brain of PD patients, all of which may result from the activation of common upstream PCD pathways. Indeed, contrary to initial views, it is now established that the deleterious effects of PCD pathways are not limited to mitochondrion-mediated caspase-dependent apoptosis but also involve caspase-independent nonapoptotic cell death, including necrosis. This notion may help reconcile the observation of both apoptotic and nonapoptotic dopaminergic cell death in postmortem PD samples. Future Directions: Potential neuroprotective strategies for PD should be aimed at targeting both apoptotic and nonapoptotic pathways, all of which may simultaneously occur in PD patients through activation of common upstream PCD pathways involving the mitochondria. © 2012, Mary Ann Liebert, Inc.