Chemical intolerance (CI) is an individual difference trait in which persons report feeling ill in multiple physiological systems from low levels of a wide range of chemically unrelated environmental substances. This paper discusses the neural sensitization model for progressive host amplification of polysymptomatic responses elicited by chemical exposures following an initiating event. The sensitization model accommodates hypotheses for initiating and eliciting CI in human populations that involve both environmental chemicals and physical or psychological stressors. Recent studies in this laboratory have demonstrated sensitization in individuals with CI over repeated sessions for dependent variables such as electroencephalographic (EEG) activity and diastolic blood pressure. Psychological distress variables alone do not explain these findings. Individuals with CI and/or vulnerability to sensitization share specific characteristics, for example, female gender, certain genetic background (offspring of alcohol-preferring parents), and personal preference for high sugar/ carbohydrate intake. Overall, the data suggest that the 15-30% of the general population who report heightened CI are highly sensitizable. Sensitizability may serve an adaptive, sentinel function in threatening environments with poor signal-to-noise ratios. However, as sensitization gradually shifts operating set points of physiological systems out of the normal range in response to allostatic load, this process may contribute to the development of chronic, polysymptomatic health conditions such as multiple chemical sensitivity and/or fibromyalgia. Individual response specificity and stereotypy rather than toxicant properties may determine which types of central, autonomic, and/or peripheral nervous system dysfunctions manifest at subclinical and clinical levels.