Oral clefts are the most common form of birth defects in the United States (US) and the State of Utah has among the highest prevalence of oral clefts in the nation. The overall objective of this dissertation was to examine the spatial distribution of oral clefts and their linkage with a broad range of demographic, behavioral, social, economic, and environmental risk factors through the application of Geographic Information Systems (GIS) and spatial statistics. Using innovative linked micromaps plots, we investigated the geographic patterns of oral clefts occurrence from 1998 to 2002 and their relationships with maternal smoking rates and proportion of American Indians and Alaskan Natives (AIAN) at large scales across the US. The findings indicated higher oral clefts occurrence in the southwest and the midwest and lower occurrence in the east. Furthermore, these spatial patterns were significantly related to the smoking rates and AIAN. Then at the small area level, hierarchical Bayesian models were built to examine the spatial variation in oral clefts risk in the State of Utah from 1995 to 2004 and to assess association with mothers using tobacco, mothers consuming alcohol during pregnancy, and the proportion of mothers with no high school diploma. Next, multi-scalar spatial clustering and cluster techniques were used to test the hypothesis whether there was spatial clustering of oral clefts anywhere in the State of Utah and whether there were statistically significant local clusters with elevated oral cleft cases. Results generally revealed modest spatial variation in oral clefts risk in the State of Utah, with no pronounced spatial clustering, indicating environmental exposures are unlikely plausible cause of oral clefts. However, a few notable areas within Tri-County Local Health District, Provo/Brigham Young University, and North Orem had a tendency toward elevated oral clefts cases. Investigation of the maternal characteristics of these potential clusters supports the hypotheses that maternal smoking, lower education level, and family history are possible causes of oral clefts. Throughout this dissertation, we demonstrated how birth defects data collected by state and local surveillance systems coupled with GIS and spatial statistics methods can be useful in exploratory etiologic research of birth defects.