This review looks at the complex interrelationship between neurotoxicant exposure, chemical metabolism, genetics and age at onset of Parkinson’s disease (PD), Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS). While the major factors influencing the onset of these age-related neurodegenerative diseases remain genetics and age per se, the role of neurotoxicant exposure as a disease modifying factor is increasingly difficult to ignore. The magnitude and duration of the exposure are the two most important factors that must be considered when investigating the relationship between neurotoxicant exposure and age at onset of neurodegenerative disease. Exposures to high concentrations readily overwhelm the ability of the body to detoxify and eliminate neurotoxicants, while chronic exposures to lower concentrations are associated with insidious cumulative effects on nervous system function. This relationship is further modified by genetic polymorphisms and factors that regulate induction of metabolic enzyme synthesis implicated in the detoxification process. With these thoughts in mind, this review explores the interactions between neurotoxicant exposure and those genetic factors that have the inherent ability to modify chemical metabolism and interaction with mechanisms implicated in the subclinical progression and age at onset of neurodegenerative disease. This review of the literature suggests that there is sufficient evidence, based on data from numerous reliable sources, to conclude that age at onset and lifetime risk for developing overt symptoms of neurodegenerative disease are modified by exposure to chemicals including neurotoxicants found in the workplace and environment and, that this relationship is further altered by genetic factors that influence pharmacokinetic and pharmacodynamics processes implicated in these diseases.