The detection of a rapidly increasing number of genetic polymorphisms in xenogen-metabolizing enzymes, of hereditary as well as acquired individual differences in DNA repair, and of the close associations between central nervous structures, the endocrine, and the immune system provides a challenge to develop an evidence-based, comprehensive model of susceptibility. Reviewing the evolution of respective approaches from 400 B.C. until today, this article proposes a conceptional framework that integrates the diverse, and sometimes puzzling contributions from all different fields of life science.