Although various episodes of wet Quaternary climates have been suggested in studies of the Negev Desert, here we demonstrate that Reg soils, developed on flat alluvial surfaces and sensitive to minor changes in precipitation, indicate that the southern Negev has been permanently hyperarid at least since the middle Pleistocene. The wetter episodes were restricted to the northern Negev, currently mildly arid. Gypsic-saline Reg soils that developed on stable surfaces during >200 k.y. in the southern Negev are cumulative and polygenetic, but none exhibits even the weakest development of calcic horizons. Under current climate conditions in the Negev, calcic soils are widespread in areas with rainfall >80 mm yr−1. The fact that the hyperarid (<50 mm yr−1) southern Negev lacks any calcic horizons indicates that it never experienced an average rainfall of ≥80 mm yr−1 during the middle-late Pleistocene, whereas the northern Negev was wetter. This Negev dichotomy is explained by the main physical features controlling rainfall over the Negev, i.e, the southward-decreasing depth of the atmospheric boundary layer with distance from the Mediterranean, and the altitude of the central Negev Highland (1000 m). The interaction between these two features often prevents the passage of rain clouds into the southern Negev. The Holocene and Pleistocene gypsic-salic soil distribution across the Negev closely matches the current circumstances. We suggest that hyperaridity has prevailed over the southern Negev since the last stages of the uplift of the central Negev Highland in the late Pliocene–early Pleistocene.