Over the last eight years, we have developed several paleoenvironmental records from a broad geographic region spanning the Altiplano in Bolivia (18°S–22°S) and continuing south along the western Andean flank to ca. 26°S. These records include: cosmogenic nuclide concentrations in surface deposits, dated nitrate paleosoils, lake levels, groundwater levels from wetland deposits, and plant macrofossils from urine-encrusted rodent middens. Arid environments are often uniquely sensitive to climate perturbations, and there is evidence of significant changes in precipitation on the western flank of the central Andes and the adjacent Altiplano. In contrast, the Atacama Desert of northern Chile is hyperarid over many millions of years. This uniquely prolonged arid climate requires the isolation of the Atacama from the Amazon Basin, a situation that has existed for more than 10 million years and that resulted from the uplift of the Andes and/or formation of the Altiplano plateau. New evidence from multiple terrestrial cosmogenic nuclides, however, suggests that overall aridity is occasionally punctuated by rare rainfall events that likely originate from the Pacific. East of the hyperarid zone, climate history from multiple proxies reveals alternating wet and dry intervals where changes in precipitation originating from the Atlantic may exceed 50%. An analysis of Pleistocene climate records across the region allows reconstruction of the spatial and temporal components of climate change. These Pleistocene wet events span the modern transition between two modes of interannual precipitation variability, and regional climate history for the Central Andean Pluvial Event (CAPE; ca. 18–8 ka) points toward similar drivers of modern interannual and past millennial-scale climate variability. The north-northeast mode of climate variability is linked to El Niño–Southern Oscillation (ENSO) variability, and the southeast mode is linked to aridity in the Chaco region of Argentina.