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Multiple chemical sensitivity syndrome (MCS) does not appear to fit established principles of toxicology. Yet social, political, and economic forces are demanding that MCS be defined medically, even though to date scientific studies have not identified pathogenic mechanisms for the condition or any objective diagnostic criteria. Consequently, a working definition of MCS can rely only on an individual's subjective symptoms of distress and attribution to environmental exposures rather than currently measurable objective evidence of disease. Nevertheless, patients labeled with MCS are clearly distressed and many are functionally disabled. In this review, four theories of causation are explored: (I) MCS is a purely biologic/physical or psychophysiologic reaction to low-level chemical exposures. (2) MCS symptoms may be elicited by low-level environmental chemical exposures, but the sensitivity is initiated by psychologic stress. (3) MCS is a misdiagnosis and chemical exposure is not the cause. The symptoms may be due to misdiagnosed physical or psychologic illness. (4) MCS is an illness belief system manifest by culturally shaped illness behavior. Areas for further research regarding the etiologies of MCS are suggested. Recognizing that the cause of the syndrome may be multifactorial, strategies are proposed for clinical evaluation and management in Part II of this manuscript using a biopsychosocial model of illness.