For more than a century, the Sangamon paleosol (the Sangamon) has been an integral part of geologic and pedologic investigations in the central United States, including the Upper Mississippi and Lower Missouri River Valleys. Compositional, pedologic, micromorphologic, stratigraphic, and age data indicate that the prominent reddish paleosol developed in silt-rich deposits of the Lower Mississippi Valley, from southernmost Illinois to northwestern Mississippi, represents multiple periods of soil formation, and is wholly or in part time equivalent to the Sangamon of the central United States. Thermoluminescence data, for localities where the Sangamon developed in loess, indicate that the primary period of loess deposition was from 190 to 130 ka (oxygen isotope stage, OIS6), that loess deposition continued intermittently from 130 to 74 ka (OIS5), and that deposition was wholly or in part coeval with Loveland loess deposition in the central United States. Beryllium-10, chemical, and pedologic data indicate that in the Lower Mississippi Valley: (1) the Sangamon represents a minimum time period of 60–80 k.y.; (2) there were at least two periods of soil formation, ca. 130–90 ka and 74–58 ka (OIS4); and (3) rates of weathering and pedogenesis equaled or exceeded the net loess-accumulation rate until at least 46 ka (OIS3) and resulted in development of a paleosol in the overlying basal Roxana Silt. Along a N-S transect from southern Illinois to western Mississippi, Sangamon macroscopic characteristics as well as the micromorphology, chemistry, and mineralogy, suggest a regional paleoclimate during periods of soil formation that: (1) was warm to hot, with a wider range in temperature, precipitation, and evapotranspiration than present; (2) had seasonal to decadal or longer periods of drought; and (3) had down-valley (southward) trends of increasing temperature and precipitation and decreasing seasonality and variation in annual to decadal precipitation.