Recent advances in Geographic Information Systems and spatial statistical and analytical methods, along with the availability of spatially referenced health and environmental data, have created unique opportunities to investigate spatial associations between environment exposures and health outcomes at multiple spatial scales and resolutions. However, the increased use of spatial data also faces challenges, one of which is to ensure certainty and accuracy of locational data that meets the needs of a study. This article critically reviews the use of spatially referenced data in epidemiologic studies, focusing on the issue of locational uncertainty generated from the process of geocoding health and environmental data. Primarily, major issues involving the use of spatially referenced data are addressed, including completeness and positional accuracy, potential source of bias and exposure misclassification, and implications for epidemiologic studies. The need for critical assessment and caution in designing and conducting spatial epidemiology studies is briefly discussed.