The Cretaceous Mancos Shale (MS) is a known nonpoint source for a significant portion of the salinity and selenium (Se) loads in the Colorado River in the southwestern United States and northwestern corner of Mexico. These two contaminants pose a serious threat to rivers in these arid regions where water supplies are especially critical. Tuttle et al. (companion paper) investigates the cycling of contaminants in a Colorado River tributary watershed (Uncompahgre River, southwestern Colorado) where the MS weathers under natural conditions. This paper builds on those results and uses regional soil data in the same watershed to investigate the impact of MS geology, weathering intensity, land use, and climate on salt and Se storage in and flux from soils on the natural landscape, irrigated agriculture fields, areas undergoing urban development, and wetlands. The size of salinity and Se reservoirs in the MS soils is quantified. Flux calculations show that during modern weathering, natural landscapes cycle salt and Se; however, little of it is released for transport to the Uncompahgre River (10% of the annual salinity and 6% of the annual Se river loads). When irrigated, salinity and Se loads from the MS soil increase (26% and 57% of the river load, respectively), causing the river to be out of compliance with Federal and State Se standards. During 100 years of irrigation, seven times more Se has been removed from agricultural soil than what was lost from natural landscapes during the entire period of pedogenesis. Under more arid conditions, even less salt and Se are expected to be transported from the natural landscape. However, if wetter climates prevail, transport could increase dramatically due to storage of soluble phases in the non-irrigated soil. These results are critical input for water-resource and land-use managers who must decide whether or not the salinity and Se in a watershed can be managed, what sustainable mitigation strategies are possible, and what landscapes should be targeted. The broader implications include providing a reliable approach for quantifying nonpoint-source contamination from MS and other rock units elsewhere that weather under similar conditions and, together with results from our companion paper, address the complex interplay of geology, weathering, climate, and land use on contaminant cycling in the arid Southwest.