One hundred sixty-seven Prairie Pothole lakes, ponds and wetlands (largely lakes) previously analyzed chemically during the late 1960’s and early to mid-1970’s were resampled and reanalyzed in 2011–2012. The two sampling periods differed climatically. The earlier sampling took place during normal to slightly dry conditions, whereas the latter occurred during and immediately following exceptionally wet conditions. As reported previously in Mushet et al. (2015), the dominant effect was expansion of the area of these lakes and dilution of their major ions. However, within that context, there were significant differences in the evolutionary pathways of major ions. To establish these pathways, we employed the inverse modeling computer code NetpathXL. This code takes the initial and final lake composition and, using mass balance constrained by the composition of diluting waters, and input and output of phases, calculates plausible geochemical evolution pathways. Despite the fact that in most cases major ions decreased, a subset of the lakes had an increase in SO₄²⁻. This distinction is significant because SO₄²⁻ is the dominant anion in a majority of Prairie Pothole Region wetlands and lakes. For lakes with decreasing SO₄²⁻, the proportion of original lake water required for mass balance was subordinate to rainwater and/or overland flow. In contrast, lakes with increasing SO₄²⁻ between the two sampling episodes tended to be dominated by original lake water. This suite of lakes tended to be smaller and have lower initial SO₄²⁻concentrations such that inputs of sulfur from dissolution of the minerals gypsum or pyrite had a significant impact on the final sulfur concentration given the lower dilution factors. Thus, our study provides context for how Prairie Pothole Region water bodies evolve geochemically as climate changes. Because wetland geochemistry in turn controls the ecology of these water bodies, this research contributes to the prediction of the impact of climate change on this important complex of ecosystems.