The first documented interpretation of the regional-scale hydrostratigraphy and groundwater flow is presented for a ~21,000-km2 area of the arsenic-affected districts of West Bengal [Murshidabad, Nadia, North 24 Parganas and South 24 Parganas (including Calcutta)], India. A hydrostratigraphic model demonstrates the presence of a continuous, semi-confined sand aquifer underlain by a thick clay aquitard. The aquifer thickens toward the east and south. In the south, discontinuous clay layers locally divide the near-surface aquifer into several deeper, laterally connected, confined aquifers. Eight 22-layer model scenarios of regional groundwater flow were developed based on the observed topography, seasonal conditions, and inferred hydrostratigraphy. The models suggest the existence of seasonally variable, regional, north–south flow across the basin prior to the onset of extensive pumping in the 1970s. Pumping has severely distorted the flow pattern, inducing high vertical hydraulic gradients across wide cones of depression. Pumping has also increased total recharge (including irrigational return flow), inflow from rivers, and sea water intrusion. Consequently, downward flow of arsenic contaminated shallow groundwater appears to have resulted in contamination of previously safe aquifers by a combination of mechanical mixing and changes in chemical equilibrium.