Trends in precipitation chemistry and hydrologic and climatic data were examined as drivers of long-term changes in the chemical composition of high-elevation lakes in three wilderness areas in Colorado during 1985–2008. Sulfate concentrations in precipitation decreased at a rate of −0.15 to −0.55 μeq/l/year at 10 high-elevation National Atmospheric Deposition Program stations in the state during 1987–2008 reflecting regional reductions in SO₂ emissions. In lakes where sulfate is primarily derived from atmospheric inputs, sulfate concentrations also decreased although the rates generally were less, ranging from −0.12 to −0.27 μeq/l/year. The similarity in timing and sulfur isotopic data support the hypothesis that decreases in atmospheric deposition are driving the response of high-elevation lakes in some areas of the state. By contrast, in lakes where sulfate is derived primarily from watershed weathering sources, sulfate concentrations showed sharp increases during 1985–2008. Analysis of long-term climate records indicates that annual air temperatures have increased between 0.45 and 0.93°C per decade throughout most mountainous areas of Colorado, suggesting climate as a factor. Isotopic data reveal that sulfate in these lakes is largely derived from pyrite, which may indicate climate warming is preferentially affecting the rate of pyrite weathering.