There is growing recognition that Parkinson's disease (PD) is likely to arise from the combined effects of genetic predisposition as well as largely unidentified environmental factors. The relative contribution of each varies from one individual to another. Even in situations where more than one family member is affected, the predominant influence may be environmental. Although responsible for only a small minority of cases of PD, recently identified genetic mutations have provided tremendous insights into the basis for neurodegeneration and have led to growing recognition of the importance of abnormal protein handling in Parkinson's as well as other neurodegenerative disorders. Abnormal protein handling may increase susceptibility to oxidative stress; conversely, numerous other factors, including oxidative stress and impaired mitochondrial function can lead to impaired protein degradation. A limited number of environmental factors are known to be toxic to the substantia nigra; in contrast, some factors such as caffeine intake and cigarette smoking may protect against the development of PD, although the mechanisms are not established. We review the various genetic and environmental factors thought to be involved in PD, as well as the mechanisms that contribute to selective nigral cell death.