The mechanism(s) underlying respiratory sensitivity to chemicals is uncertain but is assumed to involve immunologic components with pharmacologic and neurologic involvement. Predictive testing would be valuable to prevent occurrence of hypersensitivity. Several in vitro and in vivo approaches have been used for predictive purposes. In vitro methods have included assessment of the ability of the chemical to undergo reaction with proteins. Computational methods have investigated the relationship between structure and electrophilic potential of chemical allergens. We have initiated a structure-activity evaluation of chemicals associated with elicitation of respiratory sensitization and have utilized a computer-based expert system, MultiCASE. A preliminary database of 39 active chemicals has been established from a literature search of clinical case reports and animal test results. Evaluation of the model has indicated structural alerts for activity which consist of structural fragments as well as physicochemical properties. Further development of the model and evaluation of findings should enable mechanistic insight into the process of respiratory sensitization and recognition of factors which distinguish respiratory sensitizers mechanistically from other chemical allergens such as contact sensitizing chemicals.