This article describes the progression of steps followed to demonstrate a gender difference associated with Parkinson's disease (PD) and to gain an understanding of the basis, mechanisms, and implications of this gender specificity. First, a review of the literature on PD shows a greater incidence in men. Next, data are presented from a series of laboratory studies in animal models of PD that suggest a basis for this gender difference: estrogen appears to act as a neuroprotectant of the striatal dopaminergic system. One mechanism for this effect may be that estrogen inhibits the uptake of neurotoxins capable of producing degeneration within dopaminergic neurons. Finally, some of the potential neurologic implications of manipulating estrogen in premenopausal and postmenopausal women are considered.