Tilting of ancient shorelines of the Great Lakes region has been studied for more than a century. Nevertheless, fundamental disagreements exist among both glacial geologists trying to understand the chronology of lake events, geophysicists investigating the causes of tilting, and glaciologists attempting to reconstruct ice-sheet thickness along the southern perimeter of the Laurentide ice sheet. Fundamental to many of these studies is the belief that the southern part of the Great Lakes region has been geodynamically stable for at least the past 11,000 yr. Results of our numerical model of the glacio-isostatic process for a spherical, layered, self-gravitating, viscoelastic Earth suggest constraints upon Earth models, shoreline chronologies, and ice-sheet thickness. As a test of the model, predictions were compared to observations of outlet chronology and isobases of both ancient shorelines and modern tilting indicated by lake-level gauges. Earth models with a uniform-viscosity mantle resulted in the best fit to observed shorelines. Earth models with a low-viscosity asthenosphere or a high-viscosity lower mantle do not predict deformation consistent with known outlet chronologies. An ice sheet with thickness of 2,000 m over the region results in an excessive amount of tilting in most instances, whereas a much thinner ice sheet (700 m), although in better agreement with the data, generally resulted in underestimates. None of the results suggests stability in the southern Great Lakes region at any time. Predictions indicate instead that submergence of ancient shorelines has complicated the record there.