Significant advances in regional groundwater flow modeling have been driven by the demand to predict regional impacts of human inferences on groundwater systems and associated environment. The wide availability of powerful computers, user friendly modeling systems and GIS stimulates an exponential growth of regional groundwater modeling. Large scale transient groundwater models have been built to analyze regional flow systems, to simulate water budget components changes, and to optimize groundwater development scenarios. This paper reviews the historical development of regional groundwater modeling. Examples of Death Valley and Great Artesian Basin transient groundwater models are introduced to show the application of large scale regional groundwater flow models. Specific methodologies for regional groundwater flow modeling are descried and special issues in regional groundwater flow modeling are discussed