The etiology of Parkinson's disease has been enigmatic to clinicians, epidemiologists, and basic scientists since the clinical syndrome was first described in 1817. Mendelian inheritance probably accounts for a small proportion of Parkinson's disease. Apart from an increasing risk with age, the most consistent epidemiologic observation has been an inverse relation with cigarette smoking. Neither selective survival of nonsmokers nor behavioral characteristics of smokers can explain this seemingly protective association. Interest in environmental exposures, particularly pesticides, metals, and industrial solvents, heightened substantially following the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a street drug contaminant, as a cause of human parkinsonism. Epidemiologic and toxicologic research has since been guided to a great extent, although not exclusively, by mechanisms of MPTP toxicity. Efforts to characterize gene/environment interactions have also intensified in recent years. In this review, we evaluate recent evidence concerning the etiology of Parkinson's disease, with emphasis on environmental and lifestyle exposures and their potential interactions with genetic susceptibility traits. The most challenging aspects of epidemiologic research into Parkinson's disease causation include methodologic difficulties surrounding case definition, completeness of case ascertainment, selection of appropriate controls in case-control studies, and assessment of environmental exposures. We conclude with recommendations for future research directions. (Epidemiology 1999; 10:327–336)