Parkinson's disease (PD) is a common neurodegenerative disorder whose core motor symptoms are attributable to the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). The factors responsible for the selective vulnerability of these neurons have been the subject of speculations for decades. Our work has shown that these neurons are distinctive in their engagement of L-type calcium channels during autonomous pacemaking; this engagement renders them vulnerable to mitochondrial toxins used to create animal models of PD, suggesting that homeostatic calcium stress could be a key factor in the human disease. This view is buttressed by the central role of mitochondria and the endoplasmic reticulum – linchpins of current theories about the origins of PD – in calcium homeostasis, as well as epidemiological studies showing a reduced incidence of PD in patients given calcium channel antagonists. The talk will focus on these issues and new evidence linking L-type channel calcium entry and signs of mitochondrial stress. The talk will conclude with a discussion of the prospects for a neuroprotective therapy in humans.