There are, of course, a number of caveats regarding use of GIS for exposure assessment in environmental epidemiologic studies. We reviewed fundamental principles of three scientific disciplines critical to such applications: geospatial science, environmental science, and epidemiology. Axiomatic themes from each of these scientific disciplines should be adhered to in any case, but they are particularly relevant when using a GIS. These themes include accuracy and validity of data (raw and calculated), appropriate selection of mathematic formulas and models, and scientific plausibility. The application of these axiomatic themes can be very different across the scientific disciplines, which reinforces the need for multidisciplinary teams in conducting environmental epidemiology studies. For example, researchers in each of the disciplines are trained in determining the accuracy and precision of measurement data. However, only the geospatial scientist or geographer is generally trained to rectify geographic data so that two or more GIS-based data layers such as health outcome and environmental data can be merged and the resulting data layer used to determine the association more accurately. Similarly, only the epidemiologist is likely to be trained to search for and identify other data layers that, if omitted from the test of association, could confound the results.