The Atacama Desert has experienced a long and protracted period of hyperaridity that has resulted in what may be the most unusual biome on Earth, but the duration of this aridity is poorly constrained. We reconstructed aspects of the fluvial and geochemical history of this region using integrated landscape features (alluvial fans, hillslope soils, soil chemistry, river profiles) in the southern portion of the present desert. Topographic reconstructions of a large watershed (11,000 km2) show deep incision and sediment removal between the late Miocene and the end of the Pliocene, and modest to negligible incision in post-Pliocene times. These changes in incision suggest an ∼50–280× reduction in river discharge, which should reflect corresponding changes in precipitation. Changes in the nature of hillslope soils in the Atacama Desert indicate that in the Pliocene or earlier, hillslopes were mantled with silicate-derived soil. This mantle was stripped off and locally deposited as alluvial fans (late Pliocene to early Pleistocene) that now block or otherwise cause a rearrangement of Pliocene and earlier river channels. Finally, the hillslopes have largely accreted a soil mantle of dust and salt since the apparent late Pliocene stripping, suggesting a decline in annual precipitation of at least 125 mm yr−1 or more (mean annual precipitation [MAP] is now <3 mm yr−1). Embedded in the long post-Pliocene era of salt accumulation, there are a variety of features suggesting overland flow on hillslopes (rills, striped gravel deposits, piping, and water spouts) and large, infrequent storms that infiltrated gentle alluvial fans (due to the depth of salt-rich horizons). Despite evidence for episodes that punctuate the hyperaridity, the magnitude and duration of these pluvial events have been insufficient to remove the regional accumulations of sulfate, chloride, and nitrate. The late Pliocene cessation of many fluvial features is coincident with recent research on the tropical Pacific, which shows that the Pacific was in a permanent El Niño state until ca. 2.2 Ma, at which time sea-surface temperatures offshore of South America declined greatly relative to those of the western Pacific, in turn setting up the present El Niño–Southern Oscillation (ENSO) climate system. These observations indicate that the latest period of aridity has been prolonged and largely continuous, and it appears to have occurred in step with the onset of the ENSO climate system, beginning ∼2 m.y. ago.