This report is a complete description of the methods and datasets used to develop the regional model, the underlying conceptual model, and model inputs, including specified values of material properties and the assignment of external and internal boundary conditions. The report also documents the application of the SEAWAT-2000 program for variable-density flow; it details the approach, advanced methods, and results associated with calibration through nonlinear regression using the PEST program; presents the water-level, drawdown, and groundwater flows for various geographic subregions and aquifer systems; and provides analyses of the effects of pumping from shallow and deep wells on sources of water to wells, the migration of groundwater divides, and direct and indirect groundwater discharge to Lake Michigan. The report considers the role of unconfined conditions at the regional scale as well as the influence of salinity on groundwater flow. Lastly, it describes several categories of limitations and discusses ways of extending the regional model to address issues at the local scale. This regional model is intended to support the framework pilot study of water availability and use for the Great Lakes Basin. To that end, the model is designed as a platform to: allow evaluation of broad sustainability indicators for the overall groundwater regime; address the effects of future changes in water use and in climate on water availability; and host embedded refined models needed to address water-supply and ecologic issues at the local scale. Results of the simulations portray a regional groundwater-flow system that, over time, has largely maintained its natural predevelopment configuration but that locally has been strongly affected by well withdrawals. The quantity of rainfall in the Lake Michigan Basin and adjacent areas supports a dense surface-water network and recharge rates consistent with generally shallow water tables and predominantly shallow groundwater flow. At the regional scale, pumping has not caused major modifications of the shallow flow system, but it has resulted in decreases in base flow to streams and in direct discharge to Lake Michigan. On the other hand, well withdrawals have caused major reversals in regional flow patterns around pumping centers in deep, confined aquifers most noticeably in the Cambrian-Ordovician aquifer system on the west side of Lake Michigan near the cities of Green Bay and Milwaukee in eastern Wisconsin, and around Chicago in northeastern Illinois, as well as in some shallow bedrock aquifers like in the Marshall aquifer near Lansing, Michigan. The reversals in flow have been accompanied by large drawdowns with consequent local decrease in storage. On the west side of Lake Michigan, groundwater withdrawals have caused appreciable migration of the deep groundwater divides. Before the advent of pumping, the deep Lake Michigan groundwater-basin boundaries extended west of the Lake Michigan surface-water basin boundary, in some places by tens of miles. Over time, the pumping centers have replaced Lake Michigan as the regional sink for the deep flow system.